Non-invasive imaging systems and methods of use

ABSTRACT

Some embodiments of the present disclosure are directed to ultraweak photon emission imaging systems and methods. In some embodiments, a method comprises acquiring an ultraweak photon emission image of a target area of a patient for detection of a pathological condition; wherein the target area comprises an area of interest and a portion surrounding the area of interest, wherein acquiring the image comprises: enhancing formation of reactive oxygen species and/or reactive nitrogen species in the target area, wherein enhancing formation of the reactive oxygen species and/or the reactive nitrogen species comprises applying low level light illumination to the target area from 1 second to 60 minutes so as to achieve a total power output from 1 mW to 10,000 W using an average power density from 0.1 W/cm2 to 1 W/cm2; and imaging the target area, wherein imaging the target area comprises a total exposure time from 1 second to 60 minutes.

FIELD

The embodiments of the present inventions relate to medical imagingdevices and methods of use thereof.

BACKGROUND

Medical imaging can be used to detect, analyze, diagnose, prognose andmonitor pathological conditions, to recommend, support, guide and assessthe efficacy of medical treatment regimen.

SUMMARY OF INVENTION

This summary is a high-level overview of various aspects of theinvention and introduces some of the concepts that are further detailedin the Detailed Description section below. This summary is not intendedto identify key or essential features of the claimed subject matter, noris it intended to be used in isolation to determine the scope of theclaimed subject matter. The subject matter should be understood byreference to the appropriate portions of the entire specification, anyor all drawings, and each claim.

Some embodiments of the present disclosure relate to a method. In someembodiments, the method comprises acquiring an ultraweak photon emissionimage of a target area of a patient for detection of a pathologicalcondition; wherein the target area comprises an area of interest and aportion surrounding the area of interest, wherein acquiring the imagecomprises: enhancing formation of reactive oxygen species and/orreactive nitrogen species in the target area, wherein enhancingformation of the reactive oxygen species and/or the reactive nitrogenspecies comprises applying low level light illumination to the targetarea from 1 second to 60 minutes so as to achieve a total power outputfrom 1 mW to 10,000 W using an average power density from 0.1 W/cm² to 1W/cm²; and imaging the target area, wherein imaging the target areacomprises a total exposure time from 1 second to 60 minutes.

In some embodiments, applying low level light illumination comprisesusing a plurality of illumination sources.

In some embodiments, applying low level light illumination comprisesapplying a continuation light wave.

In some embodiments, applying low level light illumination comprisesapplying a pulsed light wave.

In some embodiments, the low level light illumination compriseswavelengths from 600 nm to 1100 nm.

In some embodiments, the method comprises applying red lightillumination to the target area from 1 second to 5 minutes.

In some embodiments, the method comprises applying white lightillumination to the target area from 1 second to 1 minute.

In some embodiments, enhancing formation of the reactive oxygen speciesand/or the reactive nitrogen species in the target area comprisesapplying cryotherapy, thermal therapy, fluidotherapy, hydrotherapy,ultrasound, heat lamp, diathermy, or any combination thereof to thetarget area.

Some embodiments of the present disclosure are directed to a method oftreating a chronic wound. In some embodiments, the method comprisesobtaining a sufficient amount of at least one medication for treating achronic wound based on: an acquired ultraweak photon emission image of atarget area of a patient; wherein the target area comprises an area ofinterest and a portion surrounding the area of interest, whereinacquired the ultraweak photon emission image comprises: enhancingformation of reactive oxygen species and/or reactive nitrogen species inthe target area, wherein enhancing formation of the reactive oxygenspecies and/or the reactive nitrogen species comprises applying lowlevel light illumination to the target area from 1 second to 60 minutes,and imaging the target area, wherein imaging the target area comprises atotal exposure time from 1 second to 60 minutes; a measured amount ofultraweak photon emission in area of interest in the acquired image ofthe target area; and a correlation of the measured amount of ultraweakphoton emission in the area of interest of the target area to the atleast one medication for treating the chronic wound, wherein themedication for treating the chronic wound is selected from groupconsisting of topical antibacterial, regenerative stem cells therapy,enzymes, growth factors, photodynamic treatment, or any combinationthereof; and administering the sufficient amount of at least onemedication to treat the chronic wound.

In some embodiments, applying low level light illumination to the targetarea comprises achieving a total power output from 1 mW to 10,000 Wusing an average power density from 0.1 W/cm² to 1 W/cm².

Some embodiments of the present disclosure relate to a method fortreating a chronic wound. In some embodiments, the method comprisesobtaining at least one dressing for treating a chronic wound based on:an acquired ultraweak photon emission image of a target area of apatient; wherein the target area comprises an area of interest and aportion surrounding the area of interest, wherein acquired the ultraweakphoton emission image comprises: enhancing formation of reactive oxygenspecies and/or reactive nitrogen species in the target area, whereinenhancing formation of the reactive oxygen species and/or the reactivenitrogen species comprises applying low level light illumination to thetarget area from 1 second to 60 minutes, and imaging the target area,wherein imaging the target area comprises a total exposure time from 1second to 60 minutes; a measured amount of ultraweak photon emission inarea of interest in the acquired image of the target area; and acorrelation of the measured amount of ultraweak photon emission in thearea of interest of the target area to the at least one dressing fortreating the chronic wound, wherein the dressing for treating thechronic wound is selected from group consisting of hydrogels,hydrocolloids, alginates, foam, silver impregnated dressings, artificialskin, non-adherent dressing, wet to dry dressing, silicon impregnatedatraumatic dressings, transparent film dressings, vacuum aided devices,negative pressure dressings, or any combination thereof; andadministering at least one dressing to treat the chronic wound.

Some embodiments of the present disclosure are directed to a method oftreating a chronic wound. In some embodiments, the method comprisesobtaining at least one debridement treatment for treating a chronicwound based on: an acquired ultraweak photon emission image of a targetarea of a patient; wherein the target area comprises an area of interestand a portion surrounding the area of interest, wherein acquired theultraweak photon emission image comprises: enhancing formation ofreactive oxygen species and/or reactive nitrogen species in the targetarea, wherein enhancing formation of the reactive oxygen species and/orthe reactive nitrogen species comprises applying low level lightillumination to the target area from 1 second to 60 minutes, and imagingthe target area, wherein imaging the target area comprises a totalexposure time from 1 second to 60 minutes; a measured amount ofultraweak photon emission in area of interest in the acquired image ofthe target area; and a correlation of the measured amount of ultraweakphoton emission in the area of interest of the target area to the atleast one debridement treatment for treating the chronic wound, whereinthe debridement treatment for treating the chronic wound is selectedfrom group consisting of surgical or sharp, autolytic, mechanical,chemical or enzymatic, maggot-based debridement, or any combinationthereof; and administering at least one debridement treatment to treatthe chronic wound.

Some embodiments of the present disclosure relate to a method oftreating a chronic wound. In some embodiments, the method comprisesobtaining a chronic wound reducing surgery for treating a chronic woundbased on: an acquired ultraweak photon emission image of a target areaof a patient; wherein the target area comprises an area of interest anda portion surrounding the area of interest, wherein acquired theultraweak photon emission image comprises: enhancing formation ofreactive oxygen species and/or reactive nitrogen species in the targetarea, wherein enhancing formation of the reactive oxygen species and/orthe reactive nitrogen species comprises applying low level lightillumination to the target area from 1 second to 60 minutes, and imagingthe target area, wherein imaging the target area comprises a totalexposure time from 1 second to 60 minutes; a measured amount ofultraweak photon emission in area of interest in the acquired image ofthe target area; and a correlation of the measured amount of ultraweakphoton emission in the area of interest of the target area to thechronic wound reducing surgery, wherein the surgery for treating thechronic wound is selected from group consisting of Mohs micrographicsurgery, partial amputation, corrective surgery, plastic surgery,vascular surgery, or any combination thereof; and administering thechronic wound reducing surgery to treat the chronic wound.

Some embodiments of the present disclosure are directed to a method oftreating a chronic wound. In some embodiments, the method comprisesobtaining at least one complementary therapy for treating a chronicwound based on: an acquired ultraweak photon emission image of a targetarea of a patient; wherein the target area comprises an area of interestand a portion surrounding the area of interest, wherein acquired theultraweak photon emission image comprises: enhancing formation ofreactive oxygen species and/or reactive nitrogen species in the targetarea, wherein enhancing formation of the reactive oxygen species and/orthe reactive nitrogen species comprises applying low level lightillumination to the target area from 1 second to 60 minutes, and imagingthe target area, wherein imaging the target area comprises a totalexposure time from 1 second to 60 minutes; a measured amount ofultraweak photon emission in area of interest in the acquired image ofthe target area; and a correlation of the measured amount of ultraweakphoton emission in the area of interest of the target area to the atleast one complementary therapy for treating the chronic wound, whereinthe complementary therapy for treating the chronic wound is selectedfrom group consisting of hyperbaric oxygen treatment, low-level lighttherapy, ultrasound therapy, or any combination thereof; andadministering at least one complementary therapy to treat the chronicwound.

Some embodiments of the present disclosure relate to a method oftreating cancer. In some embodiments, the method comprises obtaining acancer reducing drug for treating cancer based on: an acquired ultraweakphoton emission image of a target area of a patient; wherein the targetarea comprises an area of interest and a portion surrounding the area ofinterest, wherein acquired the ultraweak photon emission imagecomprises: enhancing formation of reactive oxygen species and/orreactive nitrogen species in the target area, wherein enhancingformation of the reactive oxygen species and/or the reactive nitrogenspecies comprises applying low level light illumination to the targetarea from 1 second to 60 minutes, and imaging the target area, whereinimaging the target area comprises a total exposure time from 1 second to60 minutes; a measured amount of ultraweak photon emission in area ofinterest in the acquired image of the target area; and a correlation ofthe measured amount of ultraweak photon emission in the area of interestof the target area to the cancer reducing drug, wherein the cancerreducing drug is selected from group consisting of chemotherapy,immunotherapy, hormone therapy, targeted drug therapy,radiopharmaceuticals, photodynamic treatment, or any combinationthereof; and administering the cancer reducing drug to treat the cancer.

Some embodiments of the present disclosure relate to a method oftreating cancer. In some embodiments, the method comprises obtaining acancer reducing surgery for treating cancer based on: an acquiredultraweak photon emission image of a target area of a patient; whereinthe target area comprises an area of interest and a portion surroundingthe area of interest, wherein acquired the ultraweak photon emissionimage comprises: enhancing formation of reactive oxygen species and/orreactive nitrogen species in the target area, wherein enhancingformation of the reactive oxygen species and/or the reactive nitrogenspecies comprises applying low level light illumination to the targetarea from 1 second to 60 minutes, and imaging the target area, whereinimaging the target area comprises a total exposure time from 1 second to60 minutes; a measured amount of ultraweak photon emission in area ofinterest in the acquired image of the target area; and a correlation ofthe measured amount of ultraweak photon emission in the area of interestof the target area to the cancer reducing surgery, wherein the cancerreducing surgery, is selected from group consisting of biopsy, staging,debulking, tumor removal, also called curative or primary surgery, orany combination thereof; and administering the cancer reducing surgeryto treat the cancer.

Some embodiments of the present disclosure are directed to a method oftreating cancer. In some embodiments, the method comprises obtaining acancer reducing radiation therapy for treating cancer based on: anacquired ultraweak photon emission image of a target area of a patient;wherein the target area comprises an area of interest and a portionsurrounding the area of interest, wherein acquired the ultraweak photonemission image comprises: enhancing formation of reactive oxygen speciesand/or reactive nitrogen species in the target area, wherein enhancingformation of the reactive oxygen species and/or the reactive nitrogenspecies comprises applying low level light illumination to the targetarea from 1 second to 60 minutes, and imaging the target area, whereinimaging the target area comprises a total exposure time from 1 second to60 minutes; a measured amount of ultraweak photon emission in area ofinterest in the acquired image of the target area; and a correlation ofthe measured amount of ultraweak photon emission in the area of interestof the target area to the cancer reducing radiation therapy, wherein thecancer reducing redacting radiation therapy, is selected from groupconsisting of external beam radiation therapy, internal radiationtherapy or any combination thereof; and administering the cancerreducing radiation therapy to treat the cancer.

Some embodiments of the present disclosure relate to a method oftreating cancer. In some embodiments, the method comprises obtaining acancer reducing ablation therapy for treating cancer based on: anacquired ultraweak photon emission image of a target area of a patient;wherein the target area comprises an area of interest and a portionsurrounding the area of interest, wherein acquired the ultraweak photonemission image comprises: enhancing formation of reactive oxygen speciesand/or reactive nitrogen species in the target area, wherein enhancingformation of the reactive oxygen species and/or the reactive nitrogenspecies comprises applying low level light illumination to the targetarea from 1 second to 60 minutes, and imaging the target area, whereinimaging the target area comprises a total exposure time from 1 second to60 minutes; a measured amount of ultraweak photon emission in area ofinterest in the acquired image of the target area; and a correlation ofthe measured amount of ultraweak photon emission in the area of interestof the target area to the cancer reducing ablation therapy, wherein thecancer reducing redacting ablation therapy, is selected from groupconsisting of cryoablation, thermal ablation, optical ablation,radiofrequency ablation, thermo-mechanical ablation, focused ultrasoundablation, or any combination thereof; and administering the cancerreducing ablation therapy to treat the cancer.

Some embodiments of the present disclosure relate to a method oftreating cardiovascular diseases. In some embodiments, the methodcomprises obtaining a drug for treating cardiovascular diseases based onan acquired ultraweak photon emission image of a target area of apatient; wherein the target area comprises an area of interest and aportion surrounding the area of interest, wherein acquired the ultraweakphoton emission image comprises: enhancing formation of reactive oxygenspecies and/or reactive nitrogen species in the target area, whereinenhancing formation of the reactive oxygen species and/or the reactivenitrogen species comprises applying low level light illumination to thetarget area from 1 second to 60 minutes, and imaging the target area,wherein imaging the target area comprises a total exposure time from 1second to 60 minutes; a measured amount of ultraweak photon emission inarea of interest in the acquired image of the target area; and acorrelation of the measured amount of ultraweak photon emission in thearea of interest of the target area to the cardiovascular diseasesreducing drug, wherein the cardiovascular diseases reducing drug isselected from group consisting of anticoagulants, aldosteroneinhibitors, antiplatelet agents and dual antiplatelet therapy,angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptorblockers, angiotensin receptor-neprilysin inhibitors, beta blockers,calcium channel blockers, cholesterol-lowering medications, digoxin,digitalis preparations, diuretics, inotropic therapy, proproteinconvertase subtilisin kexin type 9 (PCSK9) inhibitors, vasodilators,anti-inflammatory drugs, or any combination thereof; and administeringthe cardiovascular disease reducing drug to treat the cardiovasculardiseases.

Some embodiments of the present disclosure relate to a method oftreating cardiovascular diseases. In some embodiments, the methodcomprises obtaining a minimally invasive operation treatment fortreating cardiovascular diseases based on: an acquired ultraweak photonemission image of a target area of a patient; wherein the target areacomprises an area of interest and a portion surrounding the area ofinterest, wherein acquired the ultraweak photon emission imagecomprises: enhancing formation of reactive oxygen species and/orreactive nitrogen species in the target area, wherein enhancingformation of the reactive oxygen species and/or the reactive nitrogenspecies comprises applying low level light illumination to the targetarea from 1 second to 60 minutes, and imaging the target area, whereinimaging the target area comprises a total exposure time from 1 second to60 minutes; a measured amount of ultraweak photon emission in area ofinterest in the acquired image of the target area; and a correlation ofthe measured amount of ultraweak photon emission in the area of interestof the target area to the cardiovascular diseases reducing minimallyinvasive operation, wherein the cardiovascular diseases reducingminimally invasive operation is selected from group consisting ofanticoagulant therapy, coronary angioplasty, key-hole surgery, roboticsurgery, coronary artery bypass grafting, endarterectomy, hybridtherapies, or any combination thereof; and administering thecardiovascular disease reducing minimally invasive operation to treatthe cardiovascular diseases.

Some embodiments of the present disclosure relate to a method oftreating neurological disorders. In some embodiments, the methodcomprises obtaining a neurological disorder reducing drug for treatingneurological disorder based on: an acquired ultraweak photon emissionimage of a target area of a patient; wherein the target area comprisesan area of interest and a portion surrounding the area of interest,wherein acquired the ultraweak photon emission image comprises:enhancing formation of reactive oxygen species and/or reactive nitrogenspecies in the target area, wherein enhancing formation of the reactiveoxygen species and/or the reactive nitrogen species comprises applyinglow level light illumination to the target area from 1 second to 60minutes, and imaging the target area, wherein imaging the target areacomprises a total exposure time from 1 second to 60 minutes; a measuredamount of ultraweak photon emission in area of interest in the acquiredimage of the target area; and a correlation of the measured amount ofultraweak photon emission in the area of interest of the target area tothe neurological disorder reducing drug, wherein the neurologicaldisorder reducing drug is selected from group consisting of analgesics,anesthetics, anorexiants, anticonvulsants, antipyretics,antiemetic/antivertigo agents, antiparkinson agents, anxiolytics,sedatives, and hypnotics, cholinergic agonists, cholinesteraseinhibitors, CNS stimulants, drugs used in alcohol dependence, generalanesthetics, melatonin, miscellaneous central nervous system agents,muscle relaxants, neuromuscular blockers, neuroprotective agents,parasympathomimetics, psychoactive drugs, sympathomimetics, nervoussystem drug stubs, VMAT2 inhibitors, or any combination thereof; andadministering the neurological disorder reducing drug to treat theneurological disorder.

Some embodiments of the present disclosure relate to a method oftreating neurological disorders. In some embodiments, the methodcomprises obtaining a neurological disorder reducing surgery fortreating neurological disorder based on: an acquired ultraweak photonemission image of a target area of a patient; wherein the target areacomprises an area of interest and a portion surrounding the area ofinterest, wherein acquired the ultraweak photon emission imagecomprises: enhancing formation of reactive oxygen species and/orreactive nitrogen species in the target area, wherein enhancingformation of the reactive oxygen species and/or the reactive nitrogenspecies comprises applying low level light illumination to the targetarea from 1 second to 60 minutes, and imaging the target area, whereinimaging the target area comprises a total exposure time from 1 second to60 minutes; a measured amount of ultraweak photon emission in area ofinterest in the acquired image of the target area; and a correlation ofthe measured amount of ultraweak photon emission in the area of interestof the target area to the neurological disorder reducing surgery,wherein the neurological disorder reducing surgery is selected fromgroup consisting of cerebrovascular surgery including aneurysms andarteriovenous malformations (AVMs), and stroke, neuro-oncology, spinalneurosurgery, functional and epilepsy neurosurgery, generalneurosurgery, skull base surgery, trigeminal neuralgia and nervecompression syndromes, peripheral nerve injury, deep brain stimulation,radiosurgery, minimally invasive surgery, or any combination thereof;and administering the neurological disorder reducing surgery to treatthe neurological disorder.

Some embodiments of the present disclosure relate to a method oftreating neurological disorders. In some embodiments, the methodcomprises obtaining a complementary therapy for treating neurologicaldisorder based on: an acquired ultraweak photon emission image of atarget area of a patient; wherein the target area comprises an area ofinterest and a portion surrounding the area of interest, whereinacquired the ultraweak photon emission image comprises: enhancingformation of reactive oxygen species and/or reactive nitrogen species inthe target area, wherein enhancing formation of the reactive oxygenspecies and/or the reactive nitrogen species comprises applying lowlevel light illumination to the target area from 1 second to 60 minutes,and imaging the target area, wherein imaging the target area comprises atotal exposure time from 1 second to 60 minutes; a measured amount ofultraweak photon emission in area of interest in the acquired image ofthe target area; and a correlation of the measured amount of ultraweakphoton emission in the area of interest of the target area to theneurological disorder reducing complementary therapy, wherein theneurological disorder reducing complementary therapy is selected fromgroup consisting of cerebrovascular surgery including hyperbaric oxygentreatment, low level light therapy, nutrition, or any combinationthereof; and administering the neurological disorder reducingcomplementary therapy to treat the neurological disorder.

Some embodiments of the present disclosure relate to a method oftreating arthritis and other rheumatic conditions. In some embodiments,the method comprises obtaining an arthritis and other rheumaticconditions reducing drug for treating arthritis and other rheumaticconditions based on: an acquired ultraweak photon emission image of atarget area of a patient; wherein the target area comprises an area ofinterest and a portion surrounding the area of interest, whereinacquired the ultraweak photon emission image comprises: enhancingformation of reactive oxygen species and/or reactive nitrogen species inthe target area, wherein enhancing formation of the reactive oxygenspecies and/or the reactive nitrogen species comprises applying lowlevel light illumination to the target area from 1 second to 60 minutes,and imaging the target area, wherein imaging the target area comprises atotal exposure time from 1 second to 60 minutes; a measured amount ofultraweak photon emission in area of interest in the acquired image ofthe target area; and a correlation of the measured amount of ultraweakphoton emission in the area of interest of the target area to thearthritis and other rheumatic conditions reducing drug, wherein thearthritis and other rheumatic conditions reducing drug is selected fromgroup consisting of nonsteroidal anti-inflammatory drugs,counterirritants, anti-inflammatory drugs, disease-modifyingantirheumatic drugs, biologic response modifiers, steroidal drugincluding but not limited to corticosteroids, Janus Kinase (JAK)inhibitors, or any combination thereof; and administering the arthritisand other rheumatic conditions reducing drug to treat the arthritis andother rheumatic conditions.

Some embodiments of the present disclosure relate to a method oftreating arthritis and other rheumatic conditions. In some embodiments,the method comprises obtaining an arthritis and other rheumaticconditions reducing surgery for treating arthritis and other rheumaticconditions based on: an acquired ultraweak photon emission image of atarget area of a patient; wherein the target area comprises an area ofinterest and a portion surrounding the area of interest, whereinacquired the ultraweak photon emission image comprises: enhancingformation of reactive oxygen species and/or reactive nitrogen species inthe target area, wherein enhancing formation of the reactive oxygenspecies and/or the reactive nitrogen species comprises applying lowlevel light illumination to the target area from 1 second to 60 minutes,and imaging the target area, wherein imaging the target area comprises atotal exposure time from 1 second to 60 minutes; a measured amount ofultraweak photon emission in area of interest in the acquired image ofthe target area; and a correlation of the measured amount of ultraweakphoton emission in the area of interest of the target area to thearthritis and other rheumatic conditions reducing surgery, wherein thearthritis and other rheumatic conditions reducing surgery is selectedfrom group consisting of joint repair, replacement, fusion, realigningbones, lubrication injections, transcutaneous electrical nervestimulation, or any combination thereof; an administering the arthritisand other rheumatic conditions reducing surgery to treat the arthritisand other rheumatic conditions.

Some embodiments of the present disclosure relate to a method oftreating arthritis and other rheumatic conditions. In some embodiments,the method comprises obtaining a complementary therapy for treatingarthritis and other rheumatic conditions based on: an acquired ultraweakphoton emission image of a target area of a patient; wherein the targetarea comprises an area of interest and a portion surrounding the area ofinterest, wherein acquired the ultraweak photon emission imagecomprises: enhancing formation of reactive oxygen species and/orreactive nitrogen species in the target area, wherein enhancingformation of the reactive oxygen species and/or the reactive nitrogenspecies comprises applying low level light illumination to the targetarea from 1 second to 60 minutes, and imaging the target area, whereinimaging the target area comprises a total exposure time from 1 second to60 minutes; a measured amount of ultraweak photon emission in area ofinterest in the acquired image of the target area; and a correlation ofthe measured amount of ultraweak photon emission in the area of interestof the target area to the arthritis and other rheumatic conditionsreducing complementary therapy, wherein the arthritis and otherrheumatic conditions reducing surgery is selected from group consistingof physical therapy, occupational therapy, low level light therapy,nutrition, or any combination thereof; and administering the arthritisand other rheumatic conditions reducing surgery to treat the arthritisand other rheumatic conditions.

Some embodiments of the present disclosure relate to systems and methodsfor using ultraweak photon emission (UPE) imaging to measure oxidativestress in humans; analyze imaging data for detection, analysis,diagnosis, prognosis, and/or monitoring pathological conditions; supportmedical treatment by detecting and monitoring pathological conditions,guiding treatment; and assessing the efficacy of an applied treatment.

In some embodiments, UPE imaging is acquired in a passive approach,without any enhancement mechanism.

In some embodiments, the method includes steps of enhancing UPE,including but not limited to, application of low-level lightillumination (LLLI) prior to the UPE imaging. In some embodiments, themethod includes additional analysis to UPE imaging, including but notlimited to surface map reconstruction, and/or signal reconstruction,and/or incorporating into the analysis other imaging modalities.

In some embodiments, the method includes using an LLLI procedure on atarget area and using a highly sensitive detector and optical equipmentto measure the UPE of the target area. In some embodiments, themeasurement may include a long exposure to measure the UPE of the targetarea.

In some embodiments, the method includes processing of the UPE image toremove noise, correct background, apply a smoothing algorithm;identifying contours and hot spots by defined thresholds; applyingsignal reconstruction algorithms to retrieve optical-spatial details ofa deep tissue hot spot; and/or merging multiple UPE images to providedepth and spatial analysis of the pathological condition.

In some embodiments, the target area includes at least a portion of anarea of interest, and a portion of an area around the area of interest.In some embodiments, the area of interest may be the whole body, thehead and neck, part of the head and neck, the torso, part of the torso,the abdomen, part of the abdomen, and/or any organ in the body,including but not limited to, stomach, intestines, liver, gallbladder,pancreas, thyroid, lung, kidney, bladder, ovary, uterus, testicle,prostate, heart, artery or vein, lymph node, bone, bone marrow, muscle,joint, tendon, spleen, brain, brainstem, cerebellum, spine and spinalcord, connective tissue, or other.

In some embodiments, the pathological conditions may primarily beconditions which are manifested by oxidative stress. In someembodiments, the pathological conditions may be cancer tumors ormetastases in any part of the body, ischemia and/orischemia/reperfusion, cardiovascular diseases, neurological diseases,diabetes and related conditions, arthritis or other rheumaticconditions, traumatic injuries, autoimmune diseases, any condition whichmanifests inflammation, infections from bacterial, fungal, viral, orparasitic sources, and other diseases.

In some embodiments, the pathological conditions may be chronic wounds,including but not limited to diabetic (foot) ulcer, venous stasis ulcer,pressure ulcer, burn, vasculitic (leg) ulcer, and post-operativeinfection. In some embodiments, the pathological conditions may be, butnot limited to, malignant wounds of a primary cancer or a metastasis tothe skin from a local tumor or from a tumor in a distant site. In someembodiments, the pathological conditions may be, but not limited to,acute wounds, such as traumatic wounds or surgical wounds. In someembodiments, the pathological conditions may be, but not limited to,skin and soft tissue infections from bacterial, fungal, viral, orparasitic sources.

Embodiments of the present disclosure also relate to systems and methodsfor using UPE-analyzed images for early detection of pathologicalconditions to allow for early intervention. The systems and methods mayinclude using UPE-analyzed images of the same patient and the same areaof interest, taken at different times, in a comparison and contrastanalysis to provide guidance for treatment and assess the efficacy oftreatment; using UPE-analyzed images as control benchmarks, for examplefrom UPE-analyzed images from different patients with similar ordifferent pathological conditions, as well as from UPE-analyzed imagesof healthy individuals; using UPE-analyzed images and derived controlbenchmarks to improve algorithms for analysis, diagnosis, prognosis, aswell as treatment guidance and efficacy assessment.

Some embodiments of the present disclosure also relate to systems andmethods for producing LLLI by light emitting diode (LED), organic LED(OLED), solid state laser, gas laser, diode laser, incandescent lamp,halogen light source or other light sources. In some embodiments, theLLLI emitted light passes through a filter, before reaching the patient,including but not limited to, short or low pass, high or long pass, bandpass, band stop, polarizer, and any combination thereof. In someembodiments, the LLLI may include one, two or more sources, includingbut not limited to, the same type of illumination source, or differenttypes of illumination sources.

In some embodiments, the LLLI is a continuous wave (CW).

In some embodiments, the LLLI is a pulsed wave (PW) and the LLLI pulsestructure, including the pulse peak [W], the pulse width [second] andthe duty cycle (DC) [%] may vary. In some embodiments, the LLLIwavelength may vary in the range of 600-1100 nm. In some embodiments,the LLLI may include one, two or more wavelengths at the same time (witha spectral width around each central emission wavelength), from one, twoor more sources. In some embodiments, the LLLI may vary in itsirradiance [W/cm²], irradiance time [second] and therefore vary in thetotal fluence [J/cm²], and energy [J].

In some embodiments, the LLLI may be applied in contact with the skinwithout indentation in the skin, in contact with the skin with a smallindentation in the skin, or at any distance from the skin. In someembodiments, the LLLI may be applied from every direction with respectto the patient's body.

In some embodiments, the LLLI is applied through an optical waveguide,including but not limited to an optical fiber. In some embodiments, thewaveguide can be placed contact with the skin without indentation in theskin, in contact with the skin with a small indentation in the skin, orat any distance from the skin. In some embodiments, the waveguide can beplaced inside the body, including but not limited to using a catheter inany cavity in the body. In some embodiments, the LLLI is applied usingan internal wireless source including but not limited to a capsule whichcan be introduced into a static location or changing location, bydifferent means, including but not limited to minimally-invasivesurgical insertion, injection, swallowing, or other.

In some embodiments, the UPE image is acquired through no filter or oneor more filters, including but not limited to, short or low pass, highor long pass, band pass, band stop, polarizer, and any combinationthereof. In some embodiments, a series of UPE images is taken throughdifferent filters and/or no filters, and the images are each analyzedindividually, as well as compared to and/or contrasted with each other,superimposed and/or displayed. In some embodiments, the filters can beused to provide more detailed spectroscopic data. In some embodiment,different filter technologies can be used, including but not limited totunable filters.

In some embodiments, the systems and methods further includeimmobilizing the target area, part of the patient and/or the entirepatient.

In some embodiments, the systems and methods further include opticalinsulation of the target area, the area of interest, part of thepatient, the entire patient, and/or part or all the examination room.

In some embodiments, the systems and methods further include alignmentof the imaging device to the correct orientation using a dedicatedmechanical arm.

In some embodiments, the systems and methods further include placementof the optical detector directly on the skin above the measured bodypart or at a specific set distance from the skin above the measured bodypart. The spacing of the detector from the skin can be achieve by amechanical support module, including but not limited to a rigid orsemirigid shape, from any suitable material, which can support the andstabilize the optical detector as well as optically insulate the skin todetector pathway.

In some embodiments, the systems and methods further include use ofmultiple image acquisitions and/or video of the target area, part of thepatient and/or the entire patient to compensate for respiratory andother movements.

In some embodiments, the systems and methods further include movementmonitoring of the patient, either caused by breathing or other causes,using different technologies, including but not limited to passive andactive infrared thermal imaging, mechanical sensor, acoustic and/orultrasonic sensor, electromechanical sensor, laser sensor, andradiofrequency wave or microwave sensors. In some embodiments, thesystems and methods further include synchronization of the movementmonitoring to the measured UPE imaging in order the compensate for thepatient's movement.

In some embodiments, the systems and methods further includeincorporating red light (RL) illumination with and without filters,images and analyzed images; incorporating white light (WL) illuminationwith and without filters, images and analyzed images; incorporatingthree-dimensional (3D) surface reconstruction, incorporating structuredlight (SL) images and analyzed images.; and/or incorporating signalreconstruction algorithms, including but not limited to diffusion-modelbased algorithms, autocorrelation-based algorithms, combination thereof,or others. In some embodiments, the spatial matching of the UPE imagingonto the surface reconstruction map may provide better visualization foranalysis. In some embodiments, the spatially matched UPE imaging can beused as an actionable starting point for signal reconstructionalgorithms to retrieve the optical-spatial details of a deep tissuesignal.

In some embodiments, the systems and methods may include othersuperficial imaging modalities, including but not limited to, nearinfrared imaging or near infrared multispectral imaging (MSI),autofluorescence (AF) imaging, and thermal imaging, which may be used tomeasure the same target area and/or area of interest.

In some embodiments, the systems and methods may include other imagingmodalities, including but not limited to, computed tomography (CT) andmagnetic resonance imaging (MRI), which may be used to measure the sametarget area and/or area of interest.

In some embodiments, the systems and methods further include a medicalrecord system, which records all the acquired images, analyzed images,superimposed images, compare and contrast images, for every measurement,for each patient, in a secured and compliant way. In some embodiments,the systems and methods further include personalized decision supportalgorithm based on the data collected from all the measurements, and theprogression (healing/deterioration) of the pathological condition as afunction of time.

BRIEF DESCRIPTION OF THE DRAWINGS

Some embodiments of the present disclosure are herein described, by wayof example only, with reference to the accompanying drawings. Withspecific reference now to the drawings in detail, particulars shown areby way of example and for purposes of illustrative discussion of someembodiments of the invention. In this regard, the description taken withthe drawings makes apparent to those skilled in the art how embodimentsof the invention may be practiced.

FIG. 1 is an illustration of LLLI embodiments, including differentdesigns and orientations.

FIG. 2 is a flow chart illustrating an exemplary embodiment of thepresent disclosure, showing the illumination, imaging, and analysisprocedures.

FIGS. 3A and 3B are flow charts illustrating exemplary embodiments of animaging system procedure prior to imaging (FIG. 3A) and an imagingsequence (FIG. 3B).

FIG. 4 is an illustration of the UPE imaging system according to anexemplary embodiment of the present disclosure, including systemcomponents and data flow.

FIGS. 5A-F show an exemplary embodiment of a method of the presentdisclosure. FIG. 5A is an UPE raw data image after noise reduction of apost-operative infected wound in the chest. FIG. 5B is a smoothed UPEimage of FIG. 5A. FIG. 5C is a WL illumination color image of the wound.FIGS. 5D and 5E are threshold analysis of the UPE images, with twodifferent threshold levels. FIG. 5F shows the calculated contour andboundaries of the FIG. 5E threshold image.

FIGS. 6A-6C depict imaging components of an exemplary embodiment of thepresent disclosure.

FIG. 7 is a 3D illustration of UPE imaging system according to anexemplary embodiment of the present disclosure, with four imagingdevices and an adjustable mechanical apparatus.

FIG. 8 is an illustration of different orientations of an exemplary UPEimaging system.

FIGS. 9A-C show an exemplary embodiment of the present disclosure usedfor the detection of a diabetic foot ulcer. FIG. 9A is a 2D UPE image ofthe diabetic foot ulcer with a clear infection hot spot. FIG. 9B is ablack and white photo of the wound. FIG. 9C shows FIG. 9A superimposedon FIG. 9B.

FIGS. 10A-C shows an exemplary embodiment of the present disclosure usedfor venous stasis ulcer on the leg. FIG. 10A is a 2D UPE image. FIG. 10Bis a WL illumination color image of the wound. FIG. 10C shows FIG. 10Asuperimposed on FIG. 10B.

FIGS. 11A-C show an exemplary embodiment of the present disclosure usedfor the detection of a breast cancer. FIG. 11A is a 2D UPE image of thebreast cancer hot spot illustration superimposed on a black and whitesmoothed photo of a female torso. FIG. 11B is a 3D surfacereconstruction of the breasts. FIG. 11C shows the UPE signalreconstruction to the hot spot of the cancer tumor in the breast.

FIG. 12 shows an exemplary embodiment of the present disclosure used forthe detection of coronary heart disease.

FIGS. 13A-B show an exemplary embodiment of the present disclosure usedfor the detection and monitoring of a stroke. FIG. 13A is a 3D UPE imageof the head superimposed on a black and white photo of head, retrievedfrom two cameras. FIG. 13B is the UPE signal reconstruction to the hotspot of the stroke, based on 3D surface reconstruction and the UPEimages, shown via two angles: front and side view.

FIGS. 14A-D show an exemplary embodiment of the present disclosure on ahand of a patient suffering from rheumatoid arthritis. FIG. 14A is anUPE image taken without LLLI. FIG. 14B is an UPE image taken after LLLI.FIG. 14C is a black and white photo of the hand, and FIG. 14D is asuperimposed image of the LLLI enhanced UPE image (FIG. 14B) on theblack and white photo of the hand (FIG. 14C).

FIGS. 15A-D show an exemplary embodiment of the present disclosure usedas a control measurement of a wound that healed well in the patient'sheel. FIG. 15A is a 2D UPE image of the heel. FIG. 15B is a black andwhite photo of the heel. FIG. 15C shows FIG. 15A superimposed on FIG.15B. FIG. 15D is a WL illumination color image of the patient's heel andthe wound that healed well.

DETAILED DESCRIPTION

The following description of the preferred embodiment(s) is merelyexemplary in nature and is in no way intended to limit the invention,its application, or uses. As used throughout, ranges are used asshorthand for describing each and every value that is within the range.Any value within the range can be selected as the terminus of the range.In addition, all references cited herein are hereby incorporated byreferenced in their entireties. In the event of a conflict between adefinition in the present disclosure and that of a cited reference, thepresent disclosure prevails.

The description of illustrative embodiments according to principles ofthe present invention is intended to be read in connection with theaccompanying drawings, which are to be considered part of the entirewritten description. In the description of embodiments of the inventiondisclosed herein, any reference to direction or orientation is merelyintended for convenience of description and is not intended in any wayto limit the scope of the present invention.

Relative terms such as “lower,” “upper,” “horizontal,” “vertical,”“above,” “below,” “up,” “down,” “left,” “right,” “top” and “bottom” aswell as derivatives thereof (e.g., “horizontally,” “downwardly,”“upwardly,” etc.) should be construed to refer to the orientation asthen described or as shown in the drawing under discussion. Theserelative terms are for convenience of description only and do notrequire that the apparatus be constructed or operated in a particularorientation unless explicitly indicated as such.

Terms such as “attached,” “affixed,” “connected,” “coupled,”“interconnected,” “mounted” and similar refer to a relationship whereinstructures are secured or attached to one another either directly orindirectly through intervening structures, as well as both movable orrigid attachments or relationships, unless expressly describedotherwise.

As used in the specification and the claims, the singular form of “a”,“an”, and “the” include plural referents unless the context clearlydictates otherwise.

Spatial or directional terms, such as “left”, “right”, “inner”, “outer”,“above”, “below”, and the like, are not to be considered as limiting asthe invention can assume various alternative orientations.

All numbers used in the specification and claims are to be understood asbeing modified in all instances by the term “about”. The term “about”means a range of plus or minus ten percent of the stated value.

Unless otherwise indicated, all ranges or ratios disclosed herein are tobe understood to encompass any and all subranges or subratios subsumedtherein. For example, a stated range or ratio of “1 to 10” should beconsidered to include any and all subranges between (and inclusive of)the minimum value of 1 and the maximum value of 10; that is, allsubranges or subratios beginning with a minimum value of 1 or more andending with a maximum value of 10 or less, such as but not limited to, 1to 6.1, 3.5 to 7.8, and 5.5 to 10.

The terms “first”, “second”, and the like are not intended to refer toany particular order or chronology, but instead refer to differentconditions, properties, or elements.

All documents referred to herein are “incorporated by reference” intheir entirety.

The term “at least” means “greater than or equal to”. The term “notgreater than” means “less than or equal to”.

The exemplary embodiments of the present disclosure will be furtherexplained with references to the attached drawings. The drawings areschematic and illustrative in nature and are not necessarily to scale,without specific intensity bars, and provide only one version of oneexemplary embodiment of the present disclosure.

As used herein, “pathological conditions” refers to any medicalcondition at any place and/or depth in the human body, which may bemanifested by oxidative stress. In some embodiments, the pathologicalconditions may be medical conditions in the skin ranging from thesurface of the skin to a depth of about 5 mm from the surface of theskin. In some embodiments, the pathological conditions may be medicalconditions which manifest deeper than the skin. In some embodiments, thepathological conditions may be medical conditions which manifest both inthe skin and deeper than the skin.

As used herein, “target area” refers to the entire area recorded by theimaging system, which means the full frame, including parts of the imagewith nothing but background.

As used herein, “measurement” refers to the use of at least one modalityduring one continuous time frame. That means that the use of more thanone modality in sequence to another modality is still within the samemeasurement and the modalities should be effectively co-registered,assuming the imaging modalities are integrated, and the patient isstationary.

As used herein, “image”, refers to two dimensional (2D) raw dataproduced by any imaging modality. These include images produced with anytype of illumination, filtering, and exposure duration or any otherimaging parameter.

As used herein, “analyzed image” refers to an image that went through atleast one image processing procedure.

As used herein, “area of interest” refers to an area with an actual orsuspected pathological condition, which is inside the target area. Insome embodiments, the target area includes at least a portion of thearea of interest and a healthy area around or adjacent to the area ofinterest.

As used herein, the term “surface reconstruction map” refers to theconversion registration of the target area or the area of interest orany region therein. In some embodiments, the reconstruction map may bethe product of 2D structured light images, or equivalent techniques,converted to 3D representation.

As used herein, “region” refers to any area in the target area, whichmay be completely inside the area of interest, may be completely outsidethe area of interest, or may be partially inside the area of interestand partially outside the area of interest. In some embodiments, theregion can be the entire target area.

As used herein, the term “threshold” refers to an intensity of ameasured signal with a discrimination of the signal above or below it.In some embodiments, the threshold may be used to indicate a region ofpositive signal and distinguish that region from the rest of themeasured target area. In some embodiments, the region will be determinedfor one or more modalities. In some embodiments, more than one thresholdlevel will be used (i.e. multilevel threshold).

As used herein, the term “contour” refers to an outline of a specificfeature in the target area, which may be, but is not limited to, thearea of interest. In some embodiments, the contour will be determinedfor one or more modalities. In some embodiments, the contour will be theboundary of a region.

As used herein, the term “compare and contrast image” refers to ananalysis of two or more images, analyzed images, target area, area ofinterest, or regions, before or after application of surfacereconstruction map, and before or after signal reconstruction, of two ormore different measurements. In some embodiments, the two or moredifferent measurements may be of the same patient, using differentimaging modalities, and/or separated by time. “Comparing” the two ormore modalities and/or two or more measurements refers to finding theoverlaps between the two or more modalities and/or two or moremeasurements and “contrasting” refers to identifying the regions thatare not overlapping and differentiating them more clearly from theoverlapping parts as well as differentiating the other characteristicsbetween the two embodiments in the overlapping regions in term of, butnot limited to, intensity of respective signal, texture, spectralproperties, and other.

Some embodiments of the present disclosure relate to systems and methodsfor using ultraweak photon emission (UPE) imaging to measure oxidativestress in humans. UPE imaging is based on light emission associated withoxidative processes in living organisms. Although the emitted light istoo faint to be detected by the eye, every living organism emits light(electromagnetic radiation) primarily in the 300-1300 nm spectral range.This spectral range includes soft ultraviolet 315-400 nm, visible400-700 nm, and part of the near-infrared (NIR) 700-1300 nm spectrum.

As used herein, the term “enhancement” refers to any process, method,technique, or mechanism used to enhance, boost, induce, amplify, oractivate the tissue to increase the measured signal, and/or improve thesignal-to-noise (SNR), and/or result in a higher contrast betweenpathological conditions compared to healthy tissues.

As used herein, the term UPE imaging refers to both UPE imaging donepassively, meaning without any prior process, as well as UPE imagingdone after any process of enhancement, for example after low-level lightillumination.

The amount of light emitted by every living organism is significantlylarger than can be explained by thermal emission. This radiation isassociated with the formation of reactive oxygen species (ROS) andreactive nitrogen species (RNS), or collectively ROS/RNS. These chemicalspecies cause the oxidation of biomolecules, which in turn result in theformation of high-energy intermediates. These intermediate products emitlight upon relaxation to the ground state. This light is termedultra-weak photon emission or UPE. A healthy tissue will exhibit alow-level of UPE, as most of the ROS/RNS will be scavenged by adedicated antioxidant defense system of the organism. A non-limitingreview on UPE emission from living organisms, is disclosed in“Ultra-weak photon emission from biological samples: Definition,mechanisms, properties, detection and applications,” by M. Cifra and P.Pospís̆il, published in Journal of Photochemistry and Photobiology B:Biology, 139, 2 (2014), which is herein incorporated by reference in itsentirety.

Excessive formation of ROS/RNS characterizes the condition known asoxidative stress. It is closely associated with a variety of differentpathological states, including cancer, inflammation, infection,cardiovascular diseases, neurological disorders, ischemia/reperfusion,other diseases and ageing. A non-limiting review on free-radicals,oxidative stress and its relation to pathological condition is disclosedin “Free radicals and antioxidants in normal physiological functions andhuman disease”, by M. Valko, D. Leibfritz, J. Moncol, M. T. D. Cronin,M. Mazur, and J. Telser, published in The International Journal ofBiochemistry & Cell Biology, 39, 44 (2007), which is herein incorporatedby reference in its entirety.

In oxidative stress conditions, the formation of ROS/RNS exceeds thecapacity of the defense system, and UPE production is several orders ofmagnitude higher than normal—e.g., emission of 10²-10⁵ vs. 10⁻¹-10²photons/cm²s. UPE production has been measured in plant samples and in avariety of in vitro tissue samples, and in vivo surface diagnostics,using a photomultiplier tube and/or a highly sensitive camera.

Some embodiments of the present disclosure also include systems andmethods for enhancing UPE by application of low-level light illumination(LLLI) prior to the UPE imaging as well as systems and methods forproducing LLLI by light emitting diode (LED), organic LED (OLED), solidstate laser, gas laser, diode laser, incandescent lamp, halogen lightsource or other light sources. LLLI procedures may be closely related tolow-level light therapy (LLLT), also known as photobiomodulation, whichis an established field of medical research and practice, where patientsare irradiated with low-level (low power) light sources. A non-limitingreview on low-level light therapy is disclosed in “Low-level lighttherapy: photobiomodulation”, by M. R. Hamblin, C. Ferraresi, Y. Huang,L. F. de Freitas, and J. D. Carroll, published in SPIE Press, 2018Series: Tutorial texts in optical engineering, v. TT 115, which isherein incorporated by reference in its entirety.

LLLI works in different ways on the chemical and cellular level. Themain mechanism discussed in the literature is absorption of the light bycytochrome c oxidase (CCO), which is a complex IV enzyme in the electrontransport chain inside the mitochondria. LLLI increases the activity ofcomplexes I, II, III, and IV and therefore the reduction of molecularoxygen in the catalytic center of CCO, which increases the mitochondrialmembrane potential (MMP) and the levels of adenosine triphosphate (ATP),ROS, and nitric oxide (NO). Some other mechanisms and light-absorbingcellular structures have been considered. There are indications that NIRmight be absorbed by water near surfaces, which in turn change itsviscosity. Lower viscosity allows the mitochondrial rotary motor, ATPsynthase, to be more efficient, thereby increasing the electrontransport chain activity and upregulating the ATP production. Otherdownstream processes are also affected by LLLI, through multiplesignaling, ion channels, transcription factors, and biosyntheticprocesses.

The application of LLLI results in a temporary, higher formation ofROS/RNS, which is sometimes referred to as a burst. The short-term burstof ROS/RNS enhances the UPE emission intensity. The enhancement of theUPE signal enables detection of weaker and/or deeper hot spots. Giventhat the antioxidant system will likely scavenge the additional ROS/RNSmore effectively in the healthy tissue compared to the tissue underoxidative stress, the UPE enhancement from the distressed tissue isexpected to be higher. Even if the enhancement of the UPE signal fromhealthy tissue and from the pathological hot spot is comparable, becauseof the imaging devices' detection limit the additional signal wouldincrease the contrast and enable better detection of the hot spot.

The instant exemplary embodiments concern using UPE imaging to measureoxidative stress in humans, and analyzing the imaging data to detect,analyze, diagnose, prognose, and monitor pathological conditions. Theinstant exemplary embodiments can enable early detection which may allowfor timely interventions, as well as support medical treatment byproviding diagnosis and prognosis to recommend and guide treatment, andby assessing the efficacy of the applied medical treatment.

In some embodiments, the UPE spectral properties can be measured, usingdifferent filters, and used for diagnostic and prognostic purposes bydifferentiating between the spectral characteristics of differentpathological conditions (e.g. cancer vs. inflammation).

In some embodiments, UPE analyzed images of the same patient and thesame area of interest, taken at different times, are compared andcontrasted. Such a procedure may allow for direct quantification of achange in the level and distribution of the oxidative stress associatedwith the pathological condition. The change can be used as a measure forthe progression of the disease (healing/deterioration), and/or as anindication for treatment efficacy, for example: anti-inflammatorymedication for rheumatoid arthritis, antibiotic treatment for abacterial infection of a skin wound, hyperbaric oxygen treatment toreduce inflammation in the secondary phase of a traumatic brain injuryor to reduce hypoxic conditions in a chronic wound, or other, etc.

In some embodiments, UPE analyzed images of different patients withsimilar or different pathological conditions can be used to improvealgorithms for detection, diagnosis and prognosis, as well as treatmentguidance and efficacy assessment.

In some embodiments, UPE imaging is acquired using a passive approach,for example, an approach without any enhancement mechanism prior to theacquisition of the UPE image.

In some embodiments, UPE may be enhanced to acquire the images. The UPEmay be enhanced using any method known to those skilled in the art,including, for example, the application of LLLI. In an exemplaryembodiment of the present disclosure, LLLI may be configured to enhancethe signal emitted by the irradiated tissue, which would increase themeasured signal, improve the signal-to-noise (SNR) and result in ahigher contrast between pathological conditions compared to healthytissue. The enhancement of the signal enables detection andcharacterization of signal from deeper tissues, and reduction of the UPEimaging exposure time.

In some embodiments, other enhancement methods include but not limitedto cryotherapy such as ice pack, vapor coolant spray, ice massage, andcold whirlpool; thermal therapy, including conduction-based such ashydrocollator pack, low-level heat wrap, and paraffin bath,convection-based such as fluidotherapy, and hydrotherapy, andconversion-based such as ultrasound, heat lamp, and diathermy;alternating cryotherapy and thermotherapy; and other means to inducenon-harmful hormesis.

As discussed herein, LLLI can be produced by using a variety of lightsources having illumination properties that include, but are not limitedto, to continuous and pulsed sources, with different wavelengths, peakpower, pulse width and duty cycle. The illumination properties of thelight sources may be optimized to deliver the maximum enhancement of UPEsignal, reaching to the deepest relevant tissue depth, at minimum time,without over-heating the irradiated tissue. For example, illuminationsources may be chosen to maximize the LLLI energy reaching the targetarea in the patient, as maximizing the amount of LLLI may maximize theUPE signal emitted from the target area.

In some embodiments, LLLT treatments may be conducted with red or NIRlight (600-1100 nm), with a total output power of 1 mW-10,000 W using anaverage power density that does not heat the tissue (<1 W/cm², dependingon the wavelength and tissue type). For reference, a whole-body skinsurface area of an adult is on average 1.5-2 m², or 15,000-20,000 cm².In some embodiments, the LLLI is produced by, but not limited to, lightemitting diode (LED), organic LED (OLED), solid state laser, gas laser,diode laser, incandescent lamp, halogen light source, or other. In someembodiments, the LLLI emitted passes through a filter, before reachingthe patient, including but not limited to, short or low pass, high orlong pass, band pass, band stop, polarizer, and any combination thereof.In some embodiments, the LLLI may include one, two or more sources,including but not limited to, the same type of or different types ofillumination sources.

FIG. 1 depicts exemplary LLLI embodiments, including different designsand orientations of illumination sources. As shown in FIG. 1 , theillumination sources may include, but limited to, one or more lightemitting components. An illustrative embodiment of an LED bulb with 12LEDs is presented in 101. A flat panel of such units located overpatient lying supine on a bed is presented in 102 and similararrangement using a curved panel is illustrated in 103. A flat LLLIpanel irradiating from under the bed is demonstrated in 104. A smallerLLLI panel of any size is illustrated illuminating directly down at apatient in 105, or at an angel with respect to the patient in 106. Thesenon-contact embodiments are part of the exemplary embodiment. In someembodiments, the LLLI may be in contact with the skin without indentingthe skin 107, using one or more illumination sources. In someembodiments, the LLLI may be in contact the skin with a smallindentation in the skin 108. In some embodiments, the LLLI may be inapplied to the body from a light source via a waveguide, including butnot limited to an optical fiber 109. Practical illumination of largeareas would likely require illumination at some distance from the skin.In some embodiments, up to 50% of the light may be reflected back andoutside of the patient's body. Therefore, contact illumination may allowthe effective transmission of more power, because the light scatteringinto the body is more efficient. In some embodiments, small indentationinto the skin of the illuminating light source may allow for even moreefficient scattering of the light into the body. The light diffusioninto the body means that the light would penetrate deep and laterallyinto the tissue, allowing for effective illumination of internal bodyparts. As shown in FIG. 1 , in some embodiments, the LLLI may be appliedfrom every direction with respect to the patient's body.

In some embodiments, the LLLI may include a cooling unit to remove theexcess heat from the light emitting components. In some embodiments, theLLLI would be continuous wave (CW). The maximum power in CW mode islimited by excess or over heating of the tissue, which is primarilydepended on the wavelength and the tissue type. The power limiteffectively depends on the size of the irradiated area. For a pointillumination the power can be higher than a wide, or whole body,illumination.

In some embodiments, the LLLI would be pulsed wave (PW). For PW, theLLLI pulse structure, including the pulse peak [W], the pulse width[second] and the duty cycle [%] may vary. The total energy would be thepulse peak times the duty cycle times the illumination time. Thelimitation on the combination of different parameters would still beavoiding overheating of the tissue. In some embodiments, using PW, morelight may be able penetrate deeper into a patient than using CW, becausethe duty cycle allows for better thermal dissipation. Lower duty cyclecan enable higher peak power. Nominally, the peak power would be around500 mW, with 0.1 second pulse width (10 Hz), and 50% duty cycle.

In some embodiments, the LLLI wavelength may vary in the range of600-1100 nm. The most spectrally transparent range in human biologicaltissue, which is many times referred to as the NIR optical window ortherapeutic window, overlaps with this spectral range. There aredifferent definitions to the optical window, sometime defines asnarrowly as 750-900 nm. Nominally, the LLLI in use, for the deepesttissue applications, would be in the 800-850 nm range. In someembodiments, the LLLI may include one, two or more wavelengths at thesame time (with a spectral width around each central emissionwavelength), from one, two or more sources.

In some embodiments, the LLLI may vary in its irradiance [W/cm²],irradiance time [second] and therefore vary in the total fluence[J/cm²], and energy [J]. The illumination time is limited by practicalconstraints. If it is too short, the effect will be too limited. If itis too long, the patient will feel discomfort. While examination cantake up to an hour in a scan such as an MRI, for LLLT applicationillumination time may be in the range of 1 second to 60 minutes, in therange of 1 to 30 minutes, in the range of 5 to 25 minutes, and morepreferable in the range of 10-20 min. In an exemplary embodiment of thepresent disclosure, the following parameters for the illumination sourcemay be used to maximize the UPE signal emitted from a target area: PW, acombination of two sources at 600-650 nm and 800-850 nm, 500 mW/cm², 0.1second (10 Hz), 50% DC, for 600 second (10 min), which results influence of 150 J/cm².

FIG. 2 depicts a flow chart of an exemplary embodiment of the presentdisclosure, which is a method 200 for obtaining and analyzing a UPEimage. As previously discussed, in some embodiments, the method of UPEimaging and analysis is performed by passive UPE imaging, withoutenhancement. In addition, in some embodiments, including the embodimentsdiscussed in the following description, UPE imaging may follow a LLLIenhancement.

At 201 of the method 200 the preparations of the patient and of the LLLIsystem take place. Once the pre-illumination preparations are concluded,the patient is illuminated according to the specified LLLI protocol ofthe embodiment in 202. After the LLLI, the patient and the UPE imagingsystem are being prepared, in 203, for image acquisition in 204. Aftergathering all the data, the patient resumes normal function and the datacollected in 204 is analyzed in 205 to generate the output of the method206. The output of the method includes the analysis of the instantexemplary embodiments, as well as of each of the other imagingmodalities, either incorporated or physically integrated; superimposing,and compare and contrast analysis of the different imaging modalities ofthe current measurement, including surface reconstruction and signalreconstruction. In some embodiments, the system is integrated as toallow the smooth transition of the method, particularly 201 to 204without need for separate adjustment between illumination and imaging.

FIG. 3A depicts a flowchart of the pre-acquisition preparations (i.e.203). The first stage is immobilization of the target area 301. Thetarget area can be any part of the body. The relevant body part dependson the pathological condition. In some embodiments, such as wound care,the most relevant body parts may be the lower extremities, lower back ordifferent body parts. In some embodiments, such as neurology the headwould be the target area. The method of immobilization will be based onthe condition and the body part, which requires immobilization. Theimmobilization might be, but not limited to, rigid parts such assplints, more flexible parts such as strips, sheets, cushions or anyother mechanical arrangement. In some embodiments, the mechanicalimmobilization if the body part is set with respect to the imagingsystem, so that a rigid and/or semirigid mechanical separator providessupport and stabilization for the imaging system to allow imaging of themeasured body part, even with small movement of the rest of the body. Insome embodiments, the patient might be conscious, partly conscious, orunconscious. In other embodiments, the patient can be requested not tomove for duration of the measurement. In some embodiments, a movementcorrection procedure will be implemented.

Once the target area is immobilized, the optical system may be alignedto measure the target area 302. In some embodiments, this step may occurwhen the room lights are already OFF, or dimmed, or RL illumination,similar to the RL illumination of the system, in the room is ON. Inother embodiments, partial optical insulation is already over thepatient and the rough alignment is done with the system RL illumination,which is turned ON. In some embodiments, the rough alignment may beachieved by using the imaging device on video mode, with the propersettings to insure clear smooth video without saturation of the sensor.The alignment includes moving the imaging parts 405, the mechanical arm402-404, and the system unit 401 (FIG. 4 ), to enable the best alignmentof the optical components and the target area. In some embodiments, thepatient's bed or chair can be adjusted as well to help with thealignment process. In some embodiments, the rough alignment may concludewhen the target area is all, or at least mostly in focus (optimal focus)and includes at least a portion of the area of interest, and a healthyarea around or adjacent to the area of interest. In some embodiments,the system might include fixed focus optical system. In otherembodiments, the system might include an adjustable focus opticalsystem.

Following the immobilization of the patient 301 and rough alignment ofthe optical system to the target area 302, the target area may beoptically insulated. In some embodiments, the optical insulation mayinclude insulating part of, or all, the entire exam room. Once thetarget area is properly optically insulated 303, in some embodiments, itmay be required to fine-tune the optical alignment 304 prior to images'acquisition to ensure that nothing has moved during the opticalinsulation stage and as a double check that the system is ready for theclinical measurement. The fine alignment is similar to the roughalignment and is concluded when the orientation of the optical system isoptimized to the target area and the target area is in optical focus.Once these conditions are met, the fine alignment is done, and thesystem is switched from video mode to image acquisition mode. In someembodiments, mechanical immobilization provides support for the imagingsystem, including optical alignment (rough alignment, fine alignment,and focus), as well as optical insulation.

The sequence of image acquisition for physical integration multimodalityembodiment is described in FIG. 3B, where an RL illumination Image isacquired first 305, a UPE image acquired second 306, SL images areacquired third 307, and a WL illumination image is acquired forth 308.

Specifically, in some embodiments, after applying LLLI to the targetarea, the method to capture the UPE image is first to have in the rangeof 1 second to 5 minutes, in the range of 30 seconds and 2 minutes, oras a non-limiting example nominally be set to 1 minute of safe RLillumination or light tight optical insulation. This time should besufficient for relaxation of excited states in the skin and can also beused for rough optical alignment of the target area, optical insulationand fine alignment, as illustrated in FIG. 3A. Even with LLLIenhancement of the UPE, the intrinsic signal is ultra-weak and thereforea sufficiently long exposure is required for the UPE imaging. In someembodiments, the recommended total exposure time should be, in the rangeof 1 second to 60 minutes, in the range of 5 minutes to 45 minutes, orin the range of 10 minutes to 30 minutes, with a nominal time of 20minutes. Acquisition time can be reduced or optimized to the desired oracceptable SNR, with the proper choice of the optical components.

In some embodiments, the optical detection tool, may be, but is notlimited to, a charged couple device (CCD) camera that isultra-sensitive, which means the CCD has high quantum efficiency (QE,i.e. the incident photon to converted electron ratio) in the visible toNIR spectral region, or nominally 400-1000 nm. In some embodiments, thelong exposure imposes a constraint on the dark noise (dark current),which has a very strong temperature dependency. Therefore, the CCD mayneed to be cooled to a low enough temperature, as to enable properfunction with high SNR and the long exposure time. The high QErequirement across the desired spectral range may be maintained at lowoperating temperature. Different designs of sensors can be used and inparticular, but not limited to, the use of back-illuminated CCD, withdeep depletion, and anti-reflectance coating is recommended. In someembodiments, the exposure time might be divided into shorter exposures,with proportionally more readouts and their associated noise.

In some embodiments, the use of electron multiplication CCD (EMCCD),intensified CCD (ICCD), complementary metal oxide semiconductor (CMOS),and comparable devices, may be applied. In these embodiments the darknoise suppression is inferior, which imposes much shorter exposure timeslimitation, and thus in these embodiments, a low readout noise isstrongly recommended. A large sensor may enable the collection of morelight, given constraints on the optics for the utilization of the entiresensor area. In some embodiments, different sensor technologies may beused, including but not limited to solid-state multi-pixel photodiodesarray, avalanche diodes, multi-pixel photon counters (MPPC), siliconphotomultipliers (SSPM, SiPM), or other. In some embodiments, the use ofphotodetector (photosensor) of any size and configuration, down to andincluding but not limited to a single photodetector, may be used tomeasure UPE.

In some embodiments, the LLLI and imaging may alternate to maximize thesignal and/or SNR, and/or contrast, using different illumination andimaging duration and parameters. In some embodiments, the recommendedtotal alternating duration should be, in the range of 1 second to 60minutes, in the range of 5 minutes to 45 minutes, or in the range of 10minutes to 30 minutes. As a non-limiting example, the alternatingillumination and imaging sequence can be 5 minutes of illumination,followed by 5 cycles of 2 minutes imaging and 1 minute illumination fora total of 15 minutes, followed by 10 minutes imaging for a totalsequence duration of 30 minutes.

In some embodiments, in order to correct for motion of the patient, andespecially respiratory motion, different correction approaches may beapplied. In some embodiments, movement monitoring of the patient isapplied, using different technologies, including but not limited topassive and active infrared thermal imaging, mechanical sensor, acousticand/or ultrasonic sensor, electromechanical sensor, laser sensor, andradiofrequency wave or microwave sensors. These technologies may providegating or triggering data which enables synchronization of the imagingacquisition and the UPE imaging. In some embodiments, adaptivemechanical or optical tools may be used to compensate for the movement.

In some embodiments, the method further includes synchronization of themovement monitoring of the patient to the measured UPE imaging in orderthe compensate for the patient's movement using a free-breathingself-gated acquisition either during the measurement or by apost-acquisition correction. In some embodiments, because of thedifferent trade-off of the detector's thermal noise and readout noisefor movement monitoring and compensation, thereby taking many shortexposure-time images increases the dominance of minimizing readout noiseover thermal noise, different detector technologies, including but notlimited to EMCCD, ICCD, CMOS, or other, should be used.

In some embodiments, the method further includes the use ofimmobilization of the target area, or part of the patient, or the entirepatient, as demonstrated in FIG. 3A. Even with ergonomic and convenientaccommodations for the patient, there is a risk that the patient willmove during the exposure time. In such a case the UPE image would besmeared as an accumulation of the different positions of the target areaas a function of time. While it is possible and recommended to ask thepatient not to move, mechanical immobilization for the duration of themeasurement should be strongly considered. The immobilization can beimplemented is different ways, including but not limited to casts,splints, braces or collars, cushions, sheets, or other mechanicalarrangement. In some embodiments, mechanical immobilization may includerigid and/or semirigid support for the optical detector and main imagingmodule to allow minimal movement while keeping continuously imagingstability.

In some embodiments, the method further includes optical insulation ofthe target area, as demonstrated in FIG. 3A. Optical insulation mayreduce the amount of external and stray light detected by the imagingdevice. Because the UPE signal is ultra-weak, the sensor isultra-sensitive and the exposure time is long, even a weak light leakagewould affect the UPE measurement quality. The optical insulation may beachieved by the use of light absorbing or reflecting materials, alsoknown as blackout materials. Metallic components, as well as organic andsynthetic fabrics, flexible curtains, paper, rubber, cupboard, tape andother materials can be used as optical insulation materials. In someembodiments, the optical insulation also provides mechanical support forthe optical detector of the main imaging module. In some embodiments,the optical insulation will focus on the of the target area, and willalso cover, at least additional 5 cm or 2 inches, around the target arealaterally to avoid light leakage through the skin and surrounding tissueto the target area. In some embodiments, the optical insulation willcover part of the patient, the entire patient, and/or may includeoptical insulation of part of, or all, the examination room.

In some embodiments, an exemplary method further includes animage-processing procedure for noise reduction and smoothing. The mostcommon noise for UPE imaging is the so called “salt and pepper” noise,which can be mitigated by various approaches, including but not limitedto smoothing and removing outlier data points. The smoothing procedurecan be implemented in different ways, including but not limited tolinear, median, Gaussian, and low pass filtering. Another way to smooththe image, which is not entirely software based, is binning of thesensors' pixels during the image acquisition. Binning of 2×2, or higher,at the expense of spatial resolution, can yield higher sensitivity andlower variability of signal. The optimal binning also depends on thetarget area and the size of the sensor used. In some embodiments,binning is used in the UPE image acquisition, including but not limitedto 2×2, 4×4, 8×8, and 16×16.

In some embodiments, the exemplary method further includes imageprocessing for boundary-based segmentation, contour finding, and edgedetection. In some embodiments, the contour of the area of interest maybe identified and marked manually, automatically, or a combinationthereof. There may be different techniques to find edges, including butnot limited to first order derivatives (e.g. Canny, Prewitt, Sobel) andsecond order approaches. As a pre-processing step to edge detection, asmoothing stage, typically Gaussian smoothing is commonly applied. Theuse of thresholds, with different threshold levels to find edges is alsoa common practice. The threshold levels can be determined manually,automatically or a combination thereof. These image processingprocedures are illustrated in FIG. 5 .

Specifically, FIGS. 5A-F provide an example for such analysis for a UPEimage of the instant exemplary embodiments, starting with a raw imageafter noise reduction of outlier data points in FIG. 5A and smoothingprocedure of this image to produce FIG. 5B. The colors representintensity, using a jet color bar (blue to red). A WL illumination colorprocessed image in 5C of a post-operative infection wound in the chestis presented as reference for the measured image. Two different levelsof threshold applied to FIG. 5B are presented in FIG. 5D and FIG. 5E forhigh threshold and low threshold levels, respectively. Using the lowthreshold image of FIG. 5E, a contour analysis may be carried out toproduce a contour image presented in FIG. 5F.

In some embodiments, the method further includes superimposing of two ormore images or analyzed images. Each of the imaging modalities' imageand analyzed image can be superimposed onto the other, where thesuperimposed image or analyzed images undergo additional processing toset its transparency level and in some embodiments choose a specificregion to be displayed in the superimposed image without the rest of theimage or analyzed image. When superimposing embodiments from twodifferent measurements, the superimposing procedure requires theidentification and marking of reference points, which can be doneautomatically, manually or a combination thereof. The reference pointsare then used to match different images and analyzed images ontoanother, with corrections of spatial orientation, size and otherparameters. In some embodiments of the present exemplary embodiments,different optical imaging modalities can be integrated into one imagingdevice, which allows for seamless co-registration of images and analyzedimages. In these embodiments, images and analyzed images of thedifferent imaging modalities can be superimposed with high accuracy,without the need for reference points and additional correctionprocedures.

Exemplary embodiments of the present disclosure may further include aphysical integration of a UPE imaging module with other imagingmodalities modules into one imaging device, with the main detector beingthe instant exemplary embodiments' detector, i.e. the detector used tocapture UPE images with and/or without filters. In some embodiments, theother imaging modalities, with all their respectively associated modulesof illumination sources and filters may also include, but not limitedto, RL imaging, WL imaging, and SL imaging, as illustrated in FIG. 6(discussed in detail below).

In some embodiments, these additional components may be integrated indifferent geometries to achieve high-quality imaging. There are at leasttwo advantages to such integration. First, instead of having two, threeor more imaging devices, only one multi-modality device is required.Second, by using one imaging device, with the same optical settings, aseamless co-registration of all the imaging modalities is achieved. Thesame target area can be imaged, using different imaging modalities,without the need for reference points and complex analysis which isrequired when working with images and analyzed images from differentdevices. In some embodiments, the immobilization of the target area, orat least the area of interest, may become a pre-requisite in theapplication of a serial imaging scheme, as demonstrated in the methodFIG. 3A.

In some embodiments, the integrated device will use RL illuminationsource that does not optically excite the patient's body, andparticularly the skin, including but not limited to a dark red LED or afilter that removes the higher-energy shorter wavelengths (edge filter,band pass filter, or other).

In some embodiments, the method includes the physical integration of RLand WL imaging, including but not limited to LEDs arranged in a varietyof geometries. In some embodiments, the WL can be composed of acombination of blue light, green or yellow light, and red light. Thecombination of blue, green, and red lights can be used to reconstruct anatural color processed image, where the processing is only thecombination of the red, green and blue (RGB) images with the right colorbalance. In some embodiments, the WL illumination can be whiteillumination sources (broad visible spectrum), including but not limitedto LEDs. In some embodiments, the integrated device will includeadditional filters in the visible range for the WL illumination,including but not limited to red, green and blue filters, to enablenatural color processed image, where the processing is only thecombination of the filtered images with the right color balance.

In some embodiments, the method further includes the physicalintegration of SL imaging, where the SL is detected by the imagingsystem, with or without the use of one or more filters to produce anaccurate surface reconstruction map of the target area or any regiontherein. The problem SL is trying to solve is that the measured surfaceis not flat, but curved. Therefore, assessment of the area of interestarea in particular is likely inaccurate and skewed. SL is a noncontacttechnique that usually uses projected laser beams, with differentpatterns (dots, lines, or other) that distort with the curvature, depth,and irregularity of a measured surface. The mechanism creates atopographical model of the target area using at least two capturedimages with different positions of the laser beams. The implementationis not limited to laser beam but can apply to any comparable lightsource. The light source may comprise of an LED array, liquid crystaldisplay (LCD), lasers, laser diodes and/or filtered lights, and/orpolarizers, or other components arranged in a variety of geometries. Theimaging is recorded on the imaging device after passing through nofilter, or one or more different filters and/or polarizers in thevisible and NIR spectral ranges sequentially to obtain at least one ortwo images to be analyzed. The processing of the structured light imagesmay produce a surface reconstruction map, which maps the curvature ofthe measured target area to a 3D representation model, which correctsthe area of the target area, and the area of interest in particular. Insome embodiments, a similar analysis of curvature assessment andboundary detection can be implemented by illuminating lightdirectionally instead of uniformly, which means to illuminate RL and/orWL illumination, or other. Non-limiting examples of 3D mapping are alsodisclosed in “Structured-light 3D surface imaging: a tutorial”, by JasonGeng, published in Advances in Optics and Photonics 3, 128-160 (2011),which is herein incorporated by the reference in its entirety.

In some embodiments, a reconstruction map from SL images or equivalentmapping technique is incorporated in the analysis. The reconstructionmap can be used to reconstruct all other images and analyzed images,measured using other modalities to correct for the curvature of the areaof interest and/or target area. Both the original images and thecorrected images can be saved and be accessible to the users. Theprocess of this procedure is to obtain the correct measures of thepathological condition size, shape and other spatial characteristics.Correct spatial measurements may also provide a more reliable base forlongitudinal monitoring of the pathological condition.

In some embodiments, a signal reconstruction algorithm may be applied toretrieve the optical-spatial information of deep tissue signals. Thelight emitted by a hot spot deep inside the body will scatter and someof it will end up emanating from the skin. In some embodiments,primarily where the pathological condition is in the skin, orsubcutaneously close to the skin, the UPE image will represent well theunderlying pathology with minimal additional reconstruction analysis. Insome embodiments, primarily deeper into body in relatively isotropictissues, the signal reconstruction algorithm will be based on theradiative transfer equation, including but not limited to the diffusionapproximation, similar to fluorescence molecular tomography andbioluminescence tomography. In some embodiments, such as those instancesof the deepest applications with least isotropic tissues, the signalreconstruction algorithm may be based on autocorrelation reconstruction.In some embodiments, a signal reconstruction algorithm may be based on acombination of signal reconstruction algorithms mentioned, or on adifferent reconstruction algorithm.

In some embodiments, the signal reconstruction algorithm may use the 3Dmapping of the UPE signal, resulting from the surface reconstructionalgorithm, and incorporate it in the analysis. In some embodiments, thesignal reconstruction algorithm may use UPE signal collected from one,two, or more detectors, at different angles, to improve thereconstruction and allow for higher precision of the optical-spatialinformation.

In some embodiments, NIR multispectral imaging (MSI) may be incorporatedin the analysis. The purpose of the NIR MSI is to assess quantitativelythe blood flow and perfusion, and oxidation of the tissue. These tissueproperties provide an important assessment of the viability andwellbeing of the measured tissue, as they relate to the supply of oxygenand other nutrients into the tissue, as well as the removal of wasteproduct out of the tissue. Poor perfusion and lower oxidation harm thetissue and inhibit recovery. The MSI image can be further analyzed toremove noise, correct background, apply a smoothing algorithm, identifycontours, identify hot spots by defined thresholds, or undergo otherimage processing procedure. By superimposing on, and comparing andcontrasting the NIR MSI images, analyzed images and the oxidation andperfusion images with UPE imaging, a more detailed clinical profile mayemerge. The combination of these modalities may enable identification ofareas which suffer from hypoxic conditions and differentiating theseareas from other area which suffer from bacterial infection and/orinflammation without exhibiting hypoxic conditions, i.e., areas, whichexhibit high UPE signal, but normal oxidation and perfusion levels.

For example, a non-limiting embodiment is early-stage pressure injuries,in which a temporary pressure or shear reduced the blood flow and causeddamage to the tissue, but upon release the flow of blood is restored.The tissue will exhibit oxidative stress and inflammatory response,which would be detected by UPE imaging, but limited indication will bemanifested in the oxidation and perfusion images calculated from the NIRMSI. On the other hand, in a venous stasis ulcer, one expects to see anoverlap of the signals form UPE imaging and NIR MSI in the hypoxic areasof the wound. The analysis is objective and quantitative, thus requiringlimited additional interpretation.

In some embodiments, NIR MSI may also be physically integrated to theUPE imaging platform, and on the imaging device module specifically, toallow for seamless co-registration. A non-limiting embodiment of NIR MSIintegration is illustrated in FIG. 6B and FIG. 6C.

In some embodiments, autofluorescence (AF) imaging may be incorporatedin the analysis. The purpose of the AF imaging is to assess theexistence, location and severity of a bacterial infection and provide abacterial load image. The bacterial load image can be further analyzedto remove noise, correct background, apply a smoothing algorithm,identify contours, and identify hot spots by defined thresholds, orundergo other image processing procedure. By superimposing on, andcomparing and contrasting the AF images, analyzed images and thebacterial load image with UPE imaging, a more detailed clinical profilemay emerge. The combination of these modalities enables theidentifications of areas, which suffer from bacterial infection anddifferentiating these areas from other areas, which suffer from hypoxicconditions and/or inflammation without bacterial infection. For example,a non-limiting embodiment in which the bacterial infection causeshypoxic conditions or inflammation, and the UPE imaging helps identifythe most active hot spot to be treated with most care using localdebridement or application of local antibiotics. In other non-limitingembodiments, the patient may be exhibiting more than one issue. Forexample, one part of a wound may suffer from bacterial infection whileanother part may suffer from hypoxic conditions. Such clinical insightwould produce more accurate treatment plan, which may help a fasterhealing process. The analysis is objective and quantitative, thusrequiring limited additional interpretation.

In some embodiments, AF imaging may also be physically integrated to theUPE imaging platform, and on the imaging device module specifically, toallow for seamless co-registration.

In some embodiments, thermography or thermal imaging is incorporated inthe analysis. The purpose of the thermal imaging is to assess thechanges in temperature of the superficial tissue. Changes in temperatureare associated with pathological conditions. For example, inflammationwould usually exhibit higher temperature compared to healthy tissue andhypoxic conditions in the tissue would exhibit lower temperaturecompared to an adjacent healthy tissue. The thermal image, acquiredusing active or passive thermal imaging device, can be further analyzedto remove noise, correct background, apply a smoothing algorithm,identify contours, and identify hot spots by defined thresholds. Bysuperimposing on, and comparing and contrasting the thermal images,analyzed images and the thermogram (temperature image) with UPE imaging,a more detailed clinical profile may emerge. The combination of thesemodalities enables the better identifications of areas, which suffer forexample from inflammation (high temperature and high UPE signal) orhypoxia (low temperature and high UPE signal). The analysis is objectiveand quantitative, thus requiring limited additional interpretation.

The present exemplary embodiments may further include methods toincorporate in the analysis other imaging modalities' images andanalyzed images, including but not limited to, CT and MRI. Incorporatingin the analysis other imaging modalities' images and analyzed images mayprovide better visualization, and synergetic differential analysisabilities, which help detect, diagnose, prognose, as well as recommend,support, guide and assess treatment more effectively. Incorporation ofCT or MRI images in the analysis may aid in the determination of thesize, shape and other spatial characteristics of the pathologicalcondition. By combining the structural (CT, MRI) imaging modalities tothe analysis of the UPE imaging, a clinician may be able to obtain acomprehensive visualization and characterization of the pathologicalcondition. The synergetic diagnostic utility of such analysis would helpto provide the most personalized and informed treatment to patients. Byapplying this approach longitudinally, the progression of treatment maybe monitored and adjusted for optimal outcome.

UPE imaging may be viewed as a molecular imaging modality, similar insome ways to positron emission tomography (PET). In some embodiments,UPE images can be superimposed on CT or MRI images, in a similar way PETimages are superimposed on CT or MRI images. In some embodiments, amultimodality machine can be implemented, similarly to PET/CT andPET/MR, the multimodality machine may be LLLI-UPE/CT and LLLI-UPE/MR.While the potential synergy of such integration might be useful, theadvantage of the LLLI-UPE device in terms of cost and measurementwithout the use chemicals or ionizing radiation, will be diminished.

In some embodiments, the method further includes a medical recordsystem, which records all the acquired images, analyzed images, regions,superimposed images, compare and contrast images for all recordedmeasurements, for each patient, in a secured way. The medical recordsare kept in compliance with HIPAA guidelines and regulations.

In some embodiments, the method may further include using one or morepersonalized decision support algorithms based on the data collectedfrom all the measurements, for a specific condition, stage and theprogression (healing/deterioration) of the pathological condition as afunction of time. In some embodiments, the medical images can beanalyzed by various statistical tools and advanced analysis, includingbut not limited to, machine learning algorithms, deep learningalgorithms, neural networks algorithms, artificial intelligencealgorithms, or other.

An exemplary embodiment of the physical system for executing the UPEimaging methods disclosed herein is illustrated in FIG. 4 . As shown inFIG. 4 , the system may include a unit 401 that may be configured tocarry all of the mechanical, electrical, and optical components,including the computer. In some embodiments, the unit 401 may be a cart.The unit 401 may be stationary or may be configured to move.

FIG. 4 further depicts that the system includes a mechanical arm 402that is connected to the unit 401. The mechanical arm 402 may includeflexible joints 403 and a connector 404. In some embodiments, theconnector 404 has more degrees of freedom of movement than the flexiblejoint 403. As shown in FIG. 4 , an imaging module 405 may be connectedto the connector 404. The mechanical arm 402 may be configured to moveso that the imaging module 405 may be positioned in an optimal locationand orientation with respect to the patient 408.

FIGS. 6A-6C depict exemplary embodiments of the imaging module 405. Forexample, as shown in FIG. 6A, the imaging module may include an imagingcomponent 601, which may be a high sensitivity sensor or camera. In someembodiments, an optical insulation unit 606 may be attached to theimaging component 601, to ensure optimal optical insulation. In someembodiments, the optical insulation unit 606 may be part rigid and/orpart semirigid, and/or part flexible to ensure that the handling of theimaging module is convenient.

The imaging component 601 may further be connected to a lens 602, whichhas a lens cover 603. In order to achieve proper imaging on the imagingcomponent 601, the lens 602 may be placed between the patient 408 andthe imaging component 601. There are a few considerations for the choiceof lens, including (1) the materials of the lens, including the coating,have to be with low absorption in the desired spectral range (400-1000nm); (2) a compound lens, i.e. a lens system consisting of two or morelenses on the same axis, will enable full or partial correction ofdifferent aberrations, such as chromic aberration. On the other hand,more optical components means more reflection losses and more absorptionof the incident signal; (3) a larger diameter of the lens system andaperture allows for more light to go in and increase the signal, at thecost of being cumbersome, and extending the focal length and workingdistance of the lens; and (4) the working distance of the lens sets thesolid angle of target area and given the ratio of the working distanceand the aperture diameter (also known as f-number)—the numericalaperture. Therefore, there is a trade-off between how large the targetarea is and how much light can be collected efficiently.

Another consideration for choosing a lens is whether it is a fixed lensor an adjustable lens. One advantage of a fixed lens is that once focusis achieved on the entire or at least most of the target area, theworking distance is known and thus the dimensions on the target area areknown. In some embodiments, mechanical support can assist in setting areproducible and stable working distance. On the other hand, anadjustable lens may be easier to use and may require less alignmenttime. The use of an adjustable less requires either a way to knowexactly the magnification of the lens (a function that exists in somemodels of adjustable lenses) or a way to calibrate the distances on thetarget area, such as marking of known distance (marked using a ruler).

In some embodiments, the lens may be a mirror lens, which may minimizechromatic aberration and has its own tradeoffs. In some embodimentsdifferent types of lenses can be used, including but not limited tosingle or compound lens, fixed or adjustable lens, refractive or mirrorlens. In some embodiments, alternative imaging solutions may beimplemented, including but not limited to, lensless imaging, holographicimaging, polarization imaging, optical fiber, optical fiber bundle,non-imaging optics including but not limited to concentrators, acombination thereof, or other.

The imaging module 405 may further include an illumination unit 604, formultimodality physical integration embodiments. In some embodiments, theillumination unit 604 may be connected just after the lens and mayincudes illumination components for the different modalities, which isdepicted in FIG. 6B.

FIG. 6B depicts a side view 607 and a front view 608 of the illuminationunit 604. In addition, FIG. 6B depicts an exemplary embodiment of aconfiguration for the number, type and spectral range of theillumination components for the different modalities. For example, theillumination unit 604 includes WL 609, RL 610, green light 611, NIR MSIlight sources for 612, blue light for AF excitations and balanced RGBcolor imaging 613, lasers or other structured light for alignment and SLmapping 614. The arrangement, number, type, and spectral range of SL mayvary based on the embodiment. The illumination unit power may beconnected to the computer for control 409 and to an electric powersupply (not shown). In some embodiments, the illumination module mayinclude LLLI, making the enhancement and imaging integrated into asingle module.

FIG. 6C depicts an exemplary embodiment of a filter wheel 605, which maybe configured to complement the illumination unit 604 of the imagingmodule 405. In FIG. 6C, a side view 615 and a front view 616 of theillumination unit are presented. The filter wheel 605 may include oneslot without a filter 617, three filters in the visible range denoted as“V” 618, three NIR MSI in the NIR range denoted as “R” 619, two AFimaging filters in the visible and/or NIR range denoted as “F” 620, twoUPE imaging filters in the visible and/or NIR range denoted as “U” 621,and one filter in the visible and/or NIR range for structured lightdenoted as “S” 622. The arrangement, number, type, and spectral range offilters may vary based on the embodiment.

In some embodiments, the UPE spectral characteristics can be furtheranalyzed by the use of filters depicted in FIG. 6C. For example, byanalyzing the spectral characteristics of the UPE image, valuablemedical information can be retrieved, such as a differential diagnostic,as different pathological conditions have different spectral pattern(e.g. inflammation vs. cancer tumor vs. infection). In some embodiments,the filters can be used to create filtered images with spatialinformation. In other embodiments, the filters can be used to providemore detailed spectroscopic data at the expanse of the imaging,including but not limited to diffractive optical components. In someembodiment, different types of filters can be used, including but notlimited to short or low pass, high or long pass, band pass, band stop,and any combination thereof. In some embodiment, different filtertechnologies can be used, including but not limited to, differentmaterials, coatings, use of liquid crystal tunable filters (LCTF),acousto-optic tunable filters (AOTF), linear variable filters, or other.In some embodiments, a series of UPE images are taken through differentfilters or no filter. The filtered UPE image or images are thenprocessed and analyzed using the relevant image processing tools andprocedures.

In some embodiments, the UPE signal is analyzed using a spectrometerwith or without spatial filtering, to better and more completelyretrieve information from the spectral characterization of the signal.

Returning to the system depicted in FIG. 4 , optical insulation 406,including for example, blackout materials, may additionally be includedin the system, which as discussed herein, may be configured to insulatethe imaging module, the patient 408, and/or the patient's target areadesignated to imaging.

In the exemplary embodiment of FIG. 4 , a computer 409 may be positionedon the unit 401 and may be optically insulated. However, in otherembodiments, the computer 409 may be positioned outside the exam roomdue to the light emitted from the screen.

In some embodiments, the system of FIG. 4 may be positioned in anoptically insulated, enclosed space inside the examination room. Inother embodiments, the optical insulation will be confined to thesurrounding of the target area, nominally 5 cm or 2 inches around thetarget area to avoid light leakage through the skin. Optical blackoutmaterial can be used to insulate from external and stray light.

The system of FIG. 4 includes a single imaging module 405. However, insome embodiments, the system may include multiple imaging modules. Forexample, the system depicted in FIG. 7 includes multiple imaging modulesmeasuring multiple target areas, with different orientations, mounted onan adjustable mechanical support. In some embodiments, the one or moreimaging modules 405 may be positioned at different orientations withrespect to the patient, as illustrated in FIG. 7 .

Specifically, FIG. 8 depicts that measurements can be performed invarious orientations of the imaging module and of the patient. Theseorientations include, but not limited to, imaging straight down apatient lying supine 801, imaging in an angle a patient lying supine802, imaging straight up a patient lying supine 803, imaging from theside a patient lying sideways 804, imaging straight down a patient lyingprone 805, and imaging a patient lying supine from multiple orientationusing more than one imaging device 806. The optimal orientation woulddepend on the patient's condition and the pathological condition beingmeasured.

In some embodiments of the present disclosure, including the system ofFIG. 4 , may be configured to perform one or more of the followingfunctions, including, optical signal detection, signal input into aprocessing unit, and display capabilities, where the functions can beinstalled, e.g. in a dedicated procedure room or at the point of care.In some embodiments, the present exemplary embodiments are at least onemodule and are integrated into or merged with another existing or futureequipment to create a new device.

Clinical use of the exemplary systems and methods of the presentdisclosure will now be discussed. There are currently no techniques orprocedures for measuring optically, without the use chemicals(biomarkers, contrast agents, labeling compounds, radiotracers, etc.) orionizing radiation, non-invasively and locally oxidative stress in theclinical setting. While biomarkers in the blood are used to assess theholistic oxidative stress level, local detection of oxidative stressnon-invasively is not available. In many pathologic conditions,oxidative stress is deeply correlated to the pathological condition, andacts as either the cause and/or the consequence. Many times, feedbackmechanism increase the manifestation of oxidative stress (for example,infection and the inflammatory response to the infection). Thefollowing, non-limiting examples, are presented as illustrations for thebroad utility of the instant exemplary embodiments.

Exemplary embodiments of the present disclosure focus on skin and softtissue pathological conditions, including but not limited to chronicwounds such as a diabetic (foot) ulcer, venous stasis ulcer, pressureulcer, burn, vasculitic (leg) ulcer, and post-operative infection, atany stage; a chronic wound; a malignant wound, such as a primary canceror a metastasis to the skin from a local tumor or from a tumor in adistant site; a skin cancer, including but not limited to melanoma,basal cell carcinoma, squamous cell carcinoma or other; a cancermetastasis in the skin and/or subcutaneously; an acute wound such astraumatic wounds or surgical wounds, including but not limited toplastic surgery; and skin and soft tissue infections from bacterial,fungal, viral, or parasitic sources. Chronic wounds are in their essencevascular problems, which manifest oxidative stress in at least threeways: hypoxic conditions of the tissue as a result of poor perfusion ofblood and low oxidation of the tissue, infection from external bacteriaand build-up of bacterial load, and inflammation as part of the healingprocess, and as a response to, but not limited to, a bacterialinfection. Other skin wounds and other pathological conditions exhibitsimilar manifestations of oxidative stress.

In some embodiments, such as pathologic conditions involving the skinand soft tissues, it is possible to image the skin and providequantifiable and objective measure of oxidative stress, which isassociated with the pathology. The measure of the oxidative stress canbe used to differentially diagnose, prognose, recommend, support, andguide treatment regimen, and assess treatment efficacy.

In some embodiments, UPE imaging of pathological conditions involvingthe skin and soft tissues can allow for the identification of hot spots,areas with high intensity signal, which are associated with highoxidative stress. The identification of the hot spots can allow forbetter analysis and prognosis to recommend and guide better treatmentregimen. For example, if the hot spot is a result of an infection,identifying the hot spot can provide a significantly better sampling ofa bacterial infection by swabbing or biopsy, as well as follow-upmeasurements of the infected area.

FIGS. 9A-C depict an exemplary embodiment of the present disclosureusing UPE imaging for the monitoring of a diabetic foot ulcer. FIG. 9Ais an UPE image, which shows an infection hot spot in the wound. FIG. 9Bis a RL illumination image. FIG. 9C is a superposition of the UPE image(FIG. 9A) and a RL illumination image (FIG. 9B). In some embodiment, thesuperposition, illustrated in FIG. 9C, may provide better visualization,and allows and the user to easily identify the UPE active regions in thearea of interest of the target area.

In some embodiments, UPE imaging can be used for screening of differentpathological conditions to allow the application of preventivetreatment. The pathological conditions may include, but are not limitedto, venous stasis, arterial insufficiency, prolonged unrelievedpressure/sheer which can be continuous or intermitted,ischemic-reperfusion injury, and diabetes and other vascular problems,which can result in ulceration. UPE imaging can find the hot spots ofthe hypoxic and/or inflamed tissues, and direct clinical care to thoseareas. By focusing the treatment to a specific location, ulceration orat least infection of these sites may be avoided. Targeted screening andtreatment may reduce the likelihood of complications and enable fasterhealing.

In some embodiments, UPE imaging may allow for the efficacy ofadministered drugs, or other treatments, to be directly observed and/orquantified, and may further allow for better guidance for treatment,such as continuing with the current treatment, changing the dosage orother elements of the treatment, changing the type of treatment, etc. Insome embodiments, UPE imaging may allow for longitudinal assessment ofthe tissue, with the progression of the disease. In some embodiments,continuous monitoring of the same patient can be used to help assess theefficacy of treatment and help recommend, support and guide treatmentregimen. By comparing and contrasting UPE images at progressivetreatment sessions, the spread of the oxidative stress spatially and itsoverall intensity, in combination with other physiological parametersand indicators and their progression, can be assessed.

FIGS. 10A-C depict an exemplary embodiment of the present disclosureusing UPE imaging for the monitoring of a venous stasis ulcer in theleg. FIG. 10A is an UPE image, which shows hypoxic conditions hot spotsin the wound. FIG. 10B is a WL illumination color processed image. FIG.10C is a superposition of the UPE image (FIG. 10A) and the WLillumination color image (FIG. 10B). The superposition illustrated inFIG. 10C, provides better visualization, and allows the user to easilyidentify the UPE active regions in the area of interest of the targetarea.

In some embodiments, by comparing and contrasting UPE images atprogressive treatment sessions, the spread of the wound and its overallintensity, as well as other pathological conditions and theirprogression, can be assessed.

In some embodiments, UPE signal is an indication of the underlyingpathological condition of the chronic wound and can be used to recommendtreatment regimen. The treatment regimen in the case of infection mightinclude drug treatment, including, but not limited to, topicalantibacterial such as metronidazole, mupirocin, tulle, silver containingointments, anti-matrix metalloproteinases, acetic acid, hyaluronic acid,and povidone iodine, or other. Other wound care treatment procedures mayinclude, but not limited to, regenerative stem cells therapy, enzymessuch as collagenase, papain, fibrinolysism, or other, and growth factorssuch as platelet-derived growth factor, epidermal growth factor, orother. The wound care treatment regimen can also include differentdressings, including, but not limited to, hydrogels, hydrocolloids,alginates, foam, silver impregnated dressings, artificial skin,non-adherent dressing, wet to dry dressing, silicon impregnatedatraumatic dressings, transparent film dressings, vacuum aided devices,negative pressure dressings, or other. In some embodiments, there wouldbe a correlation of the measured amount of UPE signal in the area ofinterest of the target area to the at least one recommended treatmentregimen for the chronic wound.

In some embodiments, UPE can assess the effectiveness of differenttreatments to improve the condition of chronic wounds, for examplehyperbaric oxygen treatment (HBOT), and other pathological conditions.HBOT is used to reduce inflammation and hypoxic conditions in thechronic wound, and help the body fight infections, by exposing the bodyto high concentration of oxygen, up to pure (100%) oxygen, underhigh-pressure (hyperbaric) conditions. HBOT enables the body to carrymore oxygen to the chronic wound, which the wound needs to heal fasterand fight infection. The effectiveness of the treatment has largevariability. In order to allow personalized assessment for theeffectiveness of treatment, UPE imaging can measure the woundlongitudinal. A baseline measurement is taken before the first HBOTsession and compared and contrasted to subsequent sessions. The size ofthe wounds, as well as the intensity and area of the strong UPE signal,is used to assess the effectiveness of the treatment. A reduction in theUPE signal would mean an improvement in the hypoxic conditions, and/orthe inflammation, and/or the infection, which can be used as indicatorsfor the success of the treatment and encourage continuation of the HBOTregime. If the UPE imaging shows that there is no change or if there isa deterioration of the wound, then the HBOT treatment has to be modifiedand/or alternative treatment should be considered. The treatmentfeedback can be achieved within a minimal number of HBOT sessions,allowing faster healing with better allocation of treatment resources.HBOT treatment may be used in other pathological conditions, for whichUPE imaging can be used to assess the treatment effectiveness, includingbut not limited to traumatic brain injury, infection in a bone(osteomyelitis), chronic infection (actinomycosis), delayed radiationinjury, or other. In some embodiments, different treatments withvariable effectiveness, which can be analyzed using similar assessmentprocedure, include, but not limited to, photodynamic treatment,low-level light therapy, ultrasounds therapy, or other. In someembodiments, UPE signal is an indication of the underlying pathologicalcondition of the chronic wounds and can be used to recommend treatmentregimen which includes, but not limited to, hyperbaric oxygen treatment,photodynamic treatment, low-level light therapy, or other.

In some embodiments, UPE imaging can provide assessment for thewellbeing of the tissue by differentiating between healthy, stressed,and necrotic tissues, which can be used for monitoring as well andproviding surgical margins assessment to recommend appropriate treatmentregimen. As a non-limiting example, in pathological conditions such asdiabetic foot ulcers, the progression of the disease leads todeterioration of the vascular support of the foot. The tissue becomeshypoxic, with a complex inflammatory response. In case of ulceration,the body also struggles to fight infection. When the tissue deterioratesfurther, gangrene develops, and amputation becomes necessary. UPEimaging allows for longitudinal assessment of the tissue, with theprogression of the disease. When the tissue becomes unsalvageable, UPEimaging can help identify the viable tissue boundaries to allow forminimal partial amputation. UPE imaging will show the necrotic tissue asdark and the adjacent living inflamed and hypoxic tissue as bright,while the healthy tissue will have a weak consistent signal. In someembodiments, including but not limited to skin cancer, UPE imaging canbe used to provide surgical margins of the pathological condition,including, for example, in a Mohs micrographic surgery. Thus, objective,quantifiable UPE image can assist with determining the exact area andthe timing of the recommended surgical procedure. This information canreduce the trauma for the patient, expedite recovery from the surgery,and reduce the likelihood of a subsequent surgery. In some embodiments,UPE signal is an indication of the underlying pathological condition ofthe chronic wounds and can be used to recommend treatment regimen whichincludes, but not limited to, Mohs micrographic surgery, partialamputation, corrective surgery, plastic surgery, vascular surgery, orother.

In some embodiments, UPE can also assist in guiding debridement, whichinvolves the removal of dead, damaged, or infected tissue, whichimproves and promotes the healing potential of the remaining healthytissues. This common treatment procedure in wound care requiresdifferentiating between healthy, stressed and necrotic tissues. Alongwith cleaning, brushing and suction, the process of debridement,includes, but limited to, surgical or sharp, autolytic, mechanical,chemical or enzymatic, maggot-based debridement, or other. The properapplication of targeted and effective debridement, as well as assessmentof the efficacy of the procedure, can be achieved by the UPE imagingability to provide information regarding the wellbeing of the tissue atdifferent locations with suitable spatial resolution. In someembodiments, UPE signal is an indication of the underlying pathologicalcondition of the chronic wounds and can be used to recommend debridementtreatment regimen which includes, but not limited to, surgical or sharp,autolytic, mechanical, chemical, or enzymatic, maggot-based debridement,or other.

In some embodiments, after a surgery, UPE imaging can providelongitudinal measurements assessing the viability and wellbeing ofrecovering tissues. As a non-limiting example, such tracking can be usedto determine whether or not a surgical wound is healing properly withgood vascularization and the right level of inflammation, as well as toverify the absence of post-operative infection, dehiscence of skingrafts and skin flaps, and other complications which can harm thetissue, inhibit the recovery and prolong the healing process.

In some embodiments, the instant exemplary embodiments focus on cancer,primarily solid tumors, including but not limited to, bladder cancer,brain cancer, breast cancer, cervical cancer, colon and rectalendometrial cancer, kidney cancer, lip and oral cancer, liver cancer,lung (small cells and non-small cells) cancer, melanoma and nonmelanomaskin cancer, mesothelioma, oral cancer, ovarian cancer, pancreaticcancer, prostate cancer, sarcoma, thyroid cancer, or other. Chronicinflammation and oxidative stress are directly related tocarcinogenesis. Oxidative stress is also manifested in angiogenesis andchronic hypoxic conditions in the tumor microenvironment, as well asinflammatory response to the tumor. The analysis includes both theprimary tumor and metastases, in any part of the body. In someembodiments, the exemplary embodiments include measuring all stages ofcancer development, including before, during and after any treatment. Insome embodiments, UPE signal is an indication of the underlyingpathological condition of the cancer and can be used to recommendtreatment regimen including but not limited to surgery, including butnot limited to biopsy, staging, debulking, tumor removal, also calledcurative or primary surgery, medication including but not limited tochemotherapy, immunotherapy, hormone therapy, targeted drug therapy,radiopharmaceuticals, photodynamic therapy, or other, radiation therapyincluding but not limited to external beam radiation therapy, internalradiation therapy, or other, any type of ablation, including but notlimited to cryoablation, thermal ablation, optical ablation,radiofrequency ablation, thermo-mechanical ablation, focused ultrasoundablation, or other. Application of treatment is likely to have an effecton the surrounding tissue oxidative stress level, which are likely toaffect the UPE measurement. In some embodiments, there would be acorrelation of the measured amount of UPE signal in the area of interestof the target area to the at least one recommended treatment regimen forthe cancer.

FIG. 11 depicts an exemplary embodiment of the present disclosure usingUPE imaging for the detection of a breast cancer. FIG. 11A is a 2D UPEimage illustration of a female breast cancer hot spot superimposed on ablack and white smoothed photo of the patient's torso. The colorsrepresent intensity, using a jet color bar (blue to red). FIG. 11B is anillustration of 3D surface reconstruction of the breasts by using SLdata of the torso and applying the surface reconstruction algorithm.FIG. 11C shows the UPE signal reconstruction to the hot spot of thecancer tumor in the breast. The signal reconstruction algorithm uses the3D surface reconstruction and the UPE imaging as inputs and calculatesthe spatial origin of the signal deep inside the body. This allows for abetter spatial localization of the tumor for follow-up diagnostic andimaging procedures, as well as interventions, the patient is likely toneed.

In some embodiments, the instant exemplary embodiments focus oncardiovascular diseases, including but not limited to atherosclerosis,coronary heart disease, ischemic heart disease, hypertension,cardiomyopathies, cardiac hypertrophy, congestive heart failure,peripheral vascular disease, or other. These cardiovascular conditionsare highly correlated to oxidative stress. In some embodiments, theinstant exemplary embodiments focus on oxidative stress manifested inthe heart as a result of an infection, including but not limited topericarditis, endocarditis, myocarditis, or other. In some embodiments,the exemplary embodiments include measuring all stages of cardiovasculardiseases development, including before, during and after any treatment.In some embodiments, UPE signal is an indication of the underlyingpathological condition of the cardiovascular disease and can be used torecommend treatment regimen, including but not limited to medication,including but not limited to anticoagulants, aldosterone inhibitors,antiplatelet agents and dual antiplatelet therapy,angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptorblockers, angiotensin receptor-neprilysin inhibitors, beta blockers,calcium channel blockers, cholesterol-lowering medications, digoxin,digitalis preparations, diuretics, inotropic therapy, Proproteinconvertase subtilisin kexin type 9 (PCSK9) inhibitors, vasodilators,anti-inflammatory drugs, minimally invasive operations, including butnot limited to anticoagulant therapy, coronary angioplasty, key-holesurgery, robotic surgery, coronary artery bypass grafting,endarterectomy, hybrid therapies, or other. In some embodiments, therewould be a correlation of the measured amount of UPE signal in the areaof interest of the target area to the at least one recommended treatmentregimen for the cardiovascular disease.

FIG. 12 depicts an embodiment of the present exemplary embodiment'sapplication to the UPE image used for the detection of coronary heartdisease. The colors represent intensity, using a jet color bar (blue tored). The oxidative stress manifested by the coronary heart diseaseallows for early detection and intervention to avoid exacerbation andcomplications of this heart condition.

In some embodiments, the instant exemplary embodiments focus onneurological disorders, including but not limited to stroke, traumaticbrain injury, epilepsy, depression and anxiety-related disorders,schizophrenia and bipolar disorder, neurodegenerative diseases, such asAlzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,multiple sclerosis, cerebellar ataxia, Huntington's disease, dementia,or other. Oxidative damage has been identified even in early stages ofneurodegenerative diseases, indicating that their etiologies are linkedto ROS/RNS and oxidative stress. Neuroinflammation and oxidative stressare high correlated with almost all the neurological disordersmentioned. The distribution and progression of oxidative stress in thedifferent neurological disorder varies, enabling the potential fordifferentiation between the different conditions. In some embodiments,the exemplary embodiments include measuring all stages of neurologicaldisorders' development, including before, during and after anytreatment. In some embodiments, UPE signal is an indication of theunderlying pathological condition of the neurological disorder and canbe used to recommend treatment regimen, including but not limited tomedication, including but not limited to analgesics, anesthetics,anorexiants, anticonvulsants, antipyretics, antiemetic/antivertigoagents, antiparkinson agents, anxiolytics, sedatives, and hypnotics,cholinergic agonists, cholinesterase inhibitors, CNS stimulants, drugsused in alcohol dependence, general anesthetics, melatonin,miscellaneous central nervous system agents, muscle relaxants,neuromuscular blockers, neuroprotective agents, parasympathomimetics,psychoactive drugs, sympathomimetics, nervous system drug stubs, VMAT2inhibitors, or other, surgery, including but not limited tocerebrovascular surgery including aneurysms and arteriovenousmalformations (AVMs), and stroke, neuro-oncology, spinal neurosurgery,functional and epilepsy neurosurgery, general neurosurgery, skull basesurgery, trigeminal neuralgia and nerve compression syndromes,peripheral nerve injury, deep brain stimulation, radiosurgery, minimallyinvasive surgery, and complementary treatment including not limited tohyperbaric oxygen treatment, low level light therapy, nutrition, orother. In some embodiments, there would be a correlation of the measuredamount of UPE signal in the area of interest of the target area to theat least one recommended treatment regimen for the neurologicaldisorder.

FIGS. 13A-B depict an exemplary embodiment of the present disclosureusing UPE imaging for the detection and monitoring of a stroke. FIG. 13Ais a 3D UPE image of the head superimposed on a black and white photo ofhead, retrieved from two cameras. FIG. 13B is the UPE signalreconstruction to the hot spot of the stroke, based on 3D surfacereconstruction and the UPE images. The signal reconstruction allows fora spatial localization and better quantification of the strokeassociated oxidative stress for detection and monitoring applications.The photo was blurred intentionally for privacy reasons, while stillenabling the convenient localization of the stroke hot spot.

In some embodiments, the instant exemplary embodiments focus onarthritis and other rheumatic conditions, including but not limited toosteoarthritis, rheumatoid arthritis, gout, infectious arthritis,juvenile idiopathic arthritis, bursitis, fibromyalgia, polymyalgiarheumatica, polymyositis, scleroderma, systemic lupus erythematosus,tendinitis, or other. These conditions exhibit inflammation and theassociated oxidative stress. In some embodiments, the exemplaryembodiments include measuring all stages of arthritis and otherrheumatic conditions development, including before, during and after anytreatment. In some embodiments, UPE signal is an indication of theunderlying pathological condition of the arthritis and other rheumaticcondition and can be used to recommend treatment regimen including butnot limited to medication, including but not limited to nonsteroidalanti-inflammatory drugs, counterirritants, anti-inflammatory drugs,disease-modifying antirheumatic drugs, biologic response modifiers,steroidal drug including but not limited to corticosteroids, JanusKinase (JAK) inhibitors, or other, surgery, including but not limited tojoint repair, replacement, fusion, realigning bones, lubricationinjections, transcutaneous electrical nerve stimulation, or other,complementary treatment including but not limited to physical therapy,occupational therapy, low level light therapy, nutrition, or other. Insome embodiments, there would be a correlation of the measured amount ofUPE signal in the area of interest of the target area to the at leastone recommended treatment regimen for the arthritis and other rheumaticcondition.

FIGS. 14A-D depict an embodiment of the present disclosure of a hand ofa patient suffering from rheumatoid arthritis. FIG. 14A is an UPE imagetaken without LLLI enhancement, i.e., in a completely passive imageacquisition embodiment. FIG. 14B is an UPE image taken after LLLIprotocol as part of the exemplary embodiments. The colors representintensity, using a jet color bar (blue to red). Both images use the sameintensity range to illustrate the enhancement of the UPE signal by LLLI.FIG. 14C is a black and white photo of the hand, and FIG. 14D shows asuperimposition of the LLLI enhanced UPE image (FIG. 14B) on the blackand white photo of the hand (FIG. 14C). Superimposition presentationallows for a more convenient visualization of the arthritis hot spots inthe hand.

The efficacy of the administered drug, or other treatments, can bedirectly observed and/or quantified, and may further allow for betterguidance for treatment, such as continuing with the current treatment,changing the dosage or other elements of the treatment, changing thetype of treatment, etc. In some embodiments, UPE imaging may allow forlongitudinal assessment of the tissue for monitoring the progression ofthe disease, with the applied treatment.

In some embodiments, UPE imaging can be used for screening of differentpathological conditions to allow the application of preventivetreatment. For example, in some embodiments, cancerous ovarian tumorsare growing and changing the microenvironment; In some embodiments,atherosclerosis is developing into a coronary heart disease; In someembodiments, neuroinflammation is indicative of an early stage ofAlzheimer's disease. In some embodiments, UPE imaging can find the hotspots oxidative stress and direct clinical care to those areas. Byfocusing the follow up diagnostics and treatment to a specificcondition, deterioration of these conditions may be avoided. Screeningand early treatment increase the effectiveness of treatment, whilereducing the likelihood of complications, to enable faster healing.

UPE imaging has some variance based on age, complexion, nutrition,medication, and other factors. The manifestations of every pathologicalcondition also have some variance. The UPE signal associated withdifferent conditions, would change between different individuals andbetween different stages, of the same condition, even for the sameindividuals. In some embodiments, in order to establish more universalcriteria and improve the algorithms to analyze the UPE images andprovide recommendation and guidance for treatment, the method willinclude a comparison of different patients with similar conditions andwith healthy individuals. By comparing and contrasting UPE images ofdifferent patients, more generalized behavior of the UPE signal can beassigned to different pathological conditions in different stages of theillness. Comparing and contrasting UPE images of different patients maybe done, in the following non-limiting examples, to establish athreshold for hypoxic conditions which precede ulceration, establish acriterion for surgical margins of skin cancer; differentiate between theUPE signal optical and spatial characteristics of inflammation for aproperly healing surgical wounds compared to an improperly healingwound; and differentiate between UPE spectral characteristics associatedwith infection and hypoxic conditions and inflammation. For example,establishing a threshold for the UPE intensity, caused by thenon-limiting examples of infection, ischemia or cancerous tumor, wouldlikely lead to better screening procedures.

FIGS. 15A-D depict an exemplary embodiment of the present disclosureused for a control measurement. FIG. 15A shows an UPE measurement of anulcerated venous stasis wound in the patient's heel that is fullyhealed. The baseline UPE signal from the patient's heel is visible, withno observable hot spots. FIG. 15B is a RL illumination processed image.FIG. 15C shows a superimposition of the UPE image (FIG. 10A) and the RLillumination image (FIG. 15B). The superimposition illustrated in FIG.15C, provides better visualization, and allows the user to easilyidentify the UPE active regions in the area of interest of the targetarea. This result may be important as a control measurement of truenegative. A WL illumination color image in FIG. 15D is presented forreference.

It is appreciated that certain features of the disclosure, which are,for clarity, described in the context of separate embodiments, may alsobe provided in a single embodiment. Conversely, various features of thedisclosure, which are, for brevity, described in the context of a singleembodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of thedisclosure. Certain features described in the context of variousembodiments are not considered essential features of these embodiments,unless the embodiment is inoperative without those elements.

What is claimed:
 1. A method, comprising: acquiring an ultraweak photonemission image of a target area of a patient for detection of apathological condition; wherein the target area comprises an area ofinterest and a portion surrounding the area of interest, whereinacquiring the image comprises: enhancing formation of reactive oxygenspecies and/or reactive nitrogen species in the target area, whereinenhancing formation of the reactive oxygen species and/or the reactivenitrogen species comprises applying low level light illumination to thetarget area from 1 second to 60 minutes so as to achieve a total poweroutput from 1 mW to 10,000 W using an average power density from 0.1W/cm² to 1 W/cm²; and imaging the target area, wherein imaging thetarget area comprises a total exposure time from 1 second to 60 minutes.2. The method of claim 1, wherein applying low level light illuminationcomprises using a plurality of illumination sources.
 3. The method ofclaim 1, wherein applying low level light illumination comprisesapplying a continuation light wave.
 4. The method of claim 1, whereinapplying low level light illumination comprises applying a pulsed lightwave.
 5. The method of claim 1, wherein the low level light illuminationcomprises wavelengths from 600 nm to 1100 nm.
 6. The method of claim 1,further comprising applying red light illumination to the target areafrom 1 second to 5 minutes.
 7. The method of claim 1, further comprisingapplying white light illumination to the target area from 1 second to 1minute.
 8. The method of claim 1, wherein enhancing formation of thereactive oxygen species and/or the reactive nitrogen species in thetarget area comprises applying cryotherapy, thermal therapy,fluidotherapy, hydrotherapy, ultrasound, heat lamp, diathermy, or anycombination thereof to the target area.
 9. A method of treatingcardiovascular diseases, comprising: obtaining a drug for treatingcardiovascular diseases based on: an acquired ultraweak photon emissionimage of a target area of a patient; wherein the target area comprisesan area of interest and a portion surrounding the area of interest,wherein acquired the ultraweak photon emission image comprises:enhancing formation of reactive oxygen species and/or reactive nitrogenspecies in the target area,  wherein enhancing formation of the reactiveoxygen species and/or the reactive nitrogen species comprises applyinglow level light illumination to the target area from 1 second to 60minutes, and imaging the target area,  wherein imaging the target areacomprises a total exposure time from 1 second to 60 minutes; a measuredamount of ultraweak photon emission in area of interest in the acquiredimage of the target area; and a correlation of the measured amount ofultraweak photon emission in the area of interest of the target area tothe cardiovascular diseases reducing drug, wherein the cardiovasculardiseases reducing drug is selected from group consisting ofanticoagulants, aldosterone inhibitors, antiplatelet agents and dualantiplatelet therapy, angiotensin-converting enzyme (ACE) inhibitors,angiotensin II receptor blockers, angiotensin receptor-neprilysininhibitors, beta blockers, calcium channel blockers,cholesterol-lowering medications, digoxin, digitalis preparations,diuretics, inotropic therapy, proprotein convertase subtilisin kexintype 9 (PCSK9) inhibitors, vasodilators, anti-inflammatory drugs, or anycombination thereof; and administering the cardiovascular diseasereducing drug to treat the cardiovascular diseases.
 10. The method ofclaim 9, wherein applying low level light illumination to the targetarea comprises achieving a total power output from 1 mW to 10,000 Wusing an average power density from 0.1 W/cm² to 1 W/cm².
 11. A methodof treating neurological disorders, comprising: obtaining a neurologicaldisorder reducing drug for treating neurological disorder based on: anacquired ultraweak photon emission image of a target area of a patient;wherein the target area comprises an area of interest and a portionsurrounding the area of interest, wherein acquired the ultraweak photonemission image comprises: enhancing formation of reactive oxygen speciesand/or reactive nitrogen species in the target area,  wherein enhancingformation of the reactive oxygen species and/or the reactive nitrogenspecies comprises applying low level light illumination to the targetarea from 1 second to 60 minutes, and imaging the target area,  whereinimaging the target area comprises a total exposure time from 1 second to60 minutes; a measured amount of ultraweak photon emission in area ofinterest in the acquired image of the target area; and a correlation ofthe measured amount of ultraweak photon emission in the area of interestof the target area to the neurological disorder reducing drug, whereinthe neurological disorder reducing drug is selected from groupconsisting of analgesics, anesthetics, anorexiants, anticonvulsants,antipyretics, antiemetic/antivertigo agents, antiparkinson agents,anxiolytics, sedatives, and hypnotics, cholinergic agonists,cholinesterase inhibitors, CNS stimulants, drugs used in alcoholdependence, general anesthetics, melatonin, miscellaneous centralnervous system agents, muscle relaxants, neuromuscular blockers,neuroprotective agents, parasympathomimetics, psychoactive drugs,sympathomimetics, nervous system drug stubs, VMAT2 inhibitors, or anycombination thereof; and administering the neurological disorderreducing drug to treat the neurological disorder.
 12. The method ofclaim 11, wherein applying low level light illumination to the targetarea comprises achieving a total power output from 1 mW to 10,000 Wusing an average power density from 0.1 W/cm² to 1 W/cm².
 13. A methodof treating arthritis and other rheumatic conditions, comprising:obtaining an arthritis and other rheumatic conditions reducing drug fortreating arthritis and other rheumatic conditions based on: an acquiredultraweak photon emission image of a target area of a patient; whereinthe target area comprises an area of interest and a portion surroundingthe area of interest, wherein acquired the ultraweak photon emissionimage comprises: enhancing formation of reactive oxygen species and/orreactive nitrogen species in the target area,  wherein enhancingformation of the reactive oxygen species and/or the reactive nitrogenspecies comprises applying low level light illumination to the targetarea from 1 second to 60 minutes, and imaging the target area,  whereinimaging the target area comprises a total exposure time from 1 second to60 minutes; a measured amount of ultraweak photon emission in area ofinterest in the acquired image of the target area; and a correlation ofthe measured amount of ultraweak photon emission in the area of interestof the target area to the arthritis and other rheumatic conditionsreducing drug, wherein the arthritis and other rheumatic conditionsreducing drug is selected from group consisting of nonsteroidalanti-inflammatory drugs, counterirritants, anti-inflammatory drugs,disease-modifying antirheumatic drugs, biologic response modifiers,steroidal drug including but not limited to corticosteroids, JanusKinase (JAK) inhibitors, or any combination thereof; and administeringthe arthritis and other rheumatic conditions reducing drug to treat thearthritis and other rheumatic conditions.
 14. The method of claim 13,wherein applying low level light illumination to the target areacomprises achieving a total power output from 1 mW to 10,000 W using anaverage power density from 0.1 W/cm² to 1 W/cm².